Download Expression and function of cell adhesion molecules during neural

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Author/s:
MCKEOWN, SONJA; ANDERSON, RICHARD; WALLACE, ADAM
Title:
Expression and function of cell adhesion molecules during neural crest migration
Date:
2013-01-15
Citation:
McKeown, SJ; Wallace, AS; Anderson, RB, Expression and function of cell adhesion
molecules during neural crest migration, DEVELOPMENTAL BIOLOGY, 2013, 373 (2), pp.
244 - 257 (14)
Persistent Link:
http://hdl.handle.net/11343/43826
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Expression and function of cell adhesion molecules during neural crest migration
Sonja J. McKeown1, Adam S. Wallace and Richard B. Anderson
Department of Anatomy and Neuroscience, University of Melbourne, 3010, VIC,
Australia.
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Author for correspondence
Sonja McKeown
Department of Anatomy and Neuroscience
University of Melbourne
VIC 3010
Australia
[email protected]
Phone: +61383445637
Fax: +61393475219
Abstract
Neural crest cells are highly migratory cells that give rise to many derivatives
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including peripheral ganglia, craniofacial structures and melanocytes. Neural crest
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cells migrate along defined pathways to their target sites, interacting with each other
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and their environment as they migrate. Cell adhesion molecules are critical during
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this process. In this review we discuss the expression and function of cell adhesion
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molecules during the process of neural crest migration, in particular cadherins,
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integrins, members of the immunoglobulin superfamily of cell adhesion molecules,
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and the proteolytic enzymes that cleave these cell adhesion molecules.
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expression and function of these cell adhesion molecules and proteases are compared
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across neural crest emigrating from different axial levels, and across different species
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of vertebrates.
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Keywords
Neural crest, cell adhesion, migration, mouse, chick, Xenopus
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The
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Introduction
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Neural crest (NC) cells migrate extensively before giving rise to a variety of cell
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types. NC cell-cell and cell-matrix interactions are an essential part of the migration
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process. In fact, NC cell migration depends on optimal levels of adhesion, as too little
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or too much adhesion result in migration defects (Anderson et al., 2006b). In this
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review, we describe how the immunoglobulin superfamily of cell adhesion molecules
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(IgCAMs), cadherins and integrins, and the proteolytic enzymes that cleave them,
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regulate the migration of NC cells arising from different regions of the neural axis.
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NC cells form at the junction of the neural plate and epidermal ectoderm during
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neurulation. The formation of the NC requires multiple signaling pathways and
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transcription factors to establish a pool of pre-migratory neural crest cells at the dorsal
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most regions of the neural folds (Betancur et al., 2010). Once NC cells have formed,
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they undergo an epithelial-mesenchymal transition (EMT) in order to migrate away
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from the neural tube. They begin migration from the dorsal part of the neural tube
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prior to, during or after the closure of the neural tube, depending on the axial level and
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species. Cell adhesion molecules play roles in NC EMT, migration and also in their
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aggregation at their final destination, but in this review we focus primarily on the
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expression and function of cell adhesion molecules during NC migration. Changes in
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cell-cell adhesion, cell-matrix adhesion and the cell cytoskeleton during EMT have
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been reviewed recently (Clay and Halloran, 2011; Taneyhill, 2008; Thiery et al.,
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2009).
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NC cells from different anteroposterior axial levels follow different migratory
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pathways and give rise to different derivatives (Le Douarin and Kalcheim, 1999); Fig.
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1). The main sub-divisions of the neural crest are cranial, vagal and trunk. In this
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review, we discuss the role of cell adhesion molecules in regulating the migration of
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each of these NC populations. The expression and function of the main cell adhesion
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molecules are summarized in Table 1.
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Cranial Neural Crest
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Cranial NC cells give rise to much of the cartilage and bone of the skull and face, as
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well as other connective tissues, and contribute to neurons and glia in cranial ganglia.
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The cranial NC arise from the midbrain to somite 5 and migrate underneath the
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ectoderm in a ventral direction to populate the frontonasal process, branchial arches,
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and the trigeminal and epibranchial ganglia. While there is some intermingling of NC
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cells arising from different anteroposterior levels (Kulesa and Fraser, 1998), NC cells
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from particular axial levels follow pathways to populate corresponding facial
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processes (Lumsden et al., 1991; Sadaghiani and Thiebaud, 1987; Trainor et al.,
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2002). Particular cranial regions express inhibitory molecules and repel NC cells,
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narrowing the migratory pathways of NC from certain axial levels (Farlie et al., 1999;
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Golding et al., 2004). The earliest migrating cells populate the facial processes and
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give rise to mesenchymal derivatives, while later migrating NC cells remain in more
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dorsal regions and contribute to cranial ganglia (Baker et al., 1997).
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In contrast to other vertebrate species, the initial migration of cranial NC in Xenopus
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is a collective migration, followed by a wave of single cell migration (Alfandari et al.,
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2003). This collective migration process involves contact inhibition of locomotion in
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which protrusions of NC cells collapse when they contact another NC cell (Carmona-
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Fontaine et al., 2008), and collective chemotaxis, mediated by the chemokine SDF1
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(Theveneau et al., 2010). In other vertebrates, such as such as chick, time-lapse
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imaging revealed that many NC cells migrate to the branchial arches in dynamic
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chains (Kulesa and Fraser, 1998; 2000). Within these chains, the NC cells are in
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nearly constant contact with each other over short and long distances via lamellipodia
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or filopodia (Teddy and Kulesa, 2004).
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exchange cytoplasmic material through thin cellular bridges (McKinney et al., 2011).
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Cell-cell adhesion is involved in each of these modes of migration, and while N-
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cadherin has been implicated in contact inhibition of locomotion in Xenopus, the
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molecular mechanisms involved in chain migration have not yet been identified
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(Alfandari et al., 2010; Teddy and Kulesa, 2004; Theveneau et al., 2010).
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Moreover, some migrating cranial NC
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Cadherins
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The cadherin superfamily is divided into subfamilies, and of these, type I and type II
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classical cadherins, and also protocadherins have been implicated in NC development
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and migration. These cadherins are transmembrane molecules that extracellularly
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undergo primarily homophilic binding to mediate cell-cell adhesion (Gumbiner,
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2005).
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cadherins promote stronger adhesiveness than type II cadherins (Chu et al., 2006). In
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addition, some cadherins are also able to bind other molecules extracellularly
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(Gumbiner, 2005). Intracellularly, classical cadherins interact with catenins, while
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protocadherins can interact with Fyn kinases, each of which have signaling roles and
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various effects on cell behavior (Gumbiner, 2005). The role of cadherins in mediating
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cell adhesion is complex and can be regulated at many levels, both intracellularly and
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extracellularly (Halbleib and Nelson, 2006). Cadherins are involved in NC EMT,
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migration of cranial NC and the aggregation of cranial ganglia.
The strength of the cell-cell adhesion differs between cadherins: type I
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Cadherin 6B, a type II cadherin, is expressed by avian premigratory NC (Nakagawa
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and Takeichi, 1995), and is transcriptionally downregulated by Snail2 prior to
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emigration (Taneyhill et al., 2007). Cadherin-6B plays a role in the EMT undertaken
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as NC begin to migrate (Coles et al., 2007; Taneyhill, 2008).
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morpholino of cadherin-6B in chick embryos in ovo promoted premature and
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increased migration of the cranial NC, while overexpression reduced the number of
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migrating cranial NC and increased ectopic NC in the neural tube lumen in vivo, but
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not in vitro (Coles et al., 2007). These findings are different from the effect of
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manipulation of cadherin-6B in trunk NC (see below).
Inhibition by
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Expression of the type I N-cadherin by migrating avian cranial NC in vivo has not
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been detected using antibody labeling (Bronner-Fraser et al., 1992b; Duband et al.,
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1988), however, it has been detected by qPCR (McLennan et al., 2012). A possible
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explanation for this discrepancy is that processing for immunofluorescence may only
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allow visualization of N-cadherin associated with adherens junctions, and N-cadherin
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in migrating NC in vitro is mostly soluble and not associated with cell-cell contacts
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(Monier-Gavelle and Duband, 1995). In contrast, during early cranial NC migration
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in Xenopus embryos N-cadherin mRNA and protein can be detected (Theveneau et
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al., 2010), and both overexpression and morpholino knockdown of N-cadherin in vivo
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block cranial NC emigration (Theveneau et al., 2010). In vitro studies demonstrated a
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role for N-cadherin during cranial NC collective migration in Xenopus. Function
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blocking antibodies to N-cadherin prevented contact inhibition of locomotion and
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collective polarization of cranial NC cells toward an SDF1 gradient (Theveneau et al.,
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2010). Interestingly, cranial NC cells treated with an N-cadherin morpholino were
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highly motile in culture, and dispersed more rapidly than control cells (Theveneau et
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al., 2010). This behaviour is similar to migratory cardiac NC from N-cadherin null
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mutant mice, which have increased speed and persistence of movement in vitro, but
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decreased directionality (Xu et al., 2001). A model of Xenopus cranial NC migration
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has been proposed, in which N-cadherin-mediated cell adhesion causes contact-
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dependent cell polarity, and when combined with a chemotactic signal, allows
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collective chemotaxis of cranial NC (Theveneau et al., 2010).
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intracellular trafficking of N-cadherin to the cell membrane is regulated in a subset of
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cranial NC by the Wnt target gene, Ovo1, most likely through activity of Rab proteins
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(Piloto and Schilling, 2010). However loss of functional N-cadherin in the zebrafish
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pac mutant does not appear to perturb migration of cranial NC (Lele et al., 2002), and
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the impact of loss of function of N-cadherin in migrating NC in vivo in Xenopus is not
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yet known.
In zebrafish,
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Cadherin 11, a type II cadherin, is expressed by migrating cranial NC in mouse
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(Kimura et al., 1995) and Xenopus (Hadeball et al., 1998; Vallin et al., 1998). Mice
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homozygous for a mutant non-adhesive cadherin 11 have shorter frontal bones, but no
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reported cranial NC migration defects (Manabe et al., 2000), whereas inhibition of
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cadherin 11 in Xenopus in vivo revealed an important role in cranial NC migration
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(Borchers et al., 2001; Kashef et al., 2009). Knockdown of cadherin 11 inhibits NC
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migration into the second and more caudal branchial arches only, and mutant cells do
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not form filopodia or lamellipodia (Kashef et al., 2009). In vivo rescue with mutated
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versions of cadherin 11 showed that expression of the cytoplasmic tail is sufficient for
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Xenopus cranial NC migration as long as it is linked to the plasma membrane. The E-
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catenin binding site and a binding site for the guanine exchange factor Trio are critical
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intracellular domains; as over-expression of human cadherin 11, Trio or constitutively
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active small Rho GTPases rescued the loss of cadherin 11 in vivo, whereas over-
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expression of mouse cadherin 6 was unable to rescue migration (Kashef et al., 2009).
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Furthermore, cleavage of the extracellular domain of Xenopus cadherin 11 is
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necessary for cranial NC migration (see below). Thus cadherin-11 appears to act
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together with E-catenin and Trio at the plasma membrane to initiate protrusive activity
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and drive cranial NC migration through the activation of small Rho GTPases.
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Interestingly, Trio can have multiple cell surface protein partners (Backer et al., 2007;
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Briancon-Marjollet et al., 2008; Yano et al., 2011), but whether it normally binds to
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partners other than cadherin 11 in Xenopus cranial NC is not known. Xenopus cranial
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NC also express a proto-cadherin named PCNS (Rangarajan et al., 2006).
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Knockdown of PCNS by morpholino inhibits cranial NC migration in vivo and the
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cells also fail to migrate and instead disaggregrate when cultured on fibronectin
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(Rangarajan et al., 2006). The exact function of PCNS in cranial NC migration
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remains to be determined, however it has been suggested that PCNS may influence
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planar cell polarity signalling, which is required for contact inhibition of locomotion
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in Xenopus cranial NC migration (Alfandari et al., 2010).
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Avian cadherin 7, murine cadherin 6 and rat cadherin 19 are related type II cadherins
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that are expressed by migrating cranial NC (Inoue et al., 1997; Nakagawa and
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Takeichi, 1995; Takahashi and Osumi, 2005); however, a functional role has not yet
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been established, and mice null for cadherin 6 are viable with no reported cranial NC
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defects (Mah et al., 2000). Cadherin 7 expression has recently been shown to be
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expressed at higher levels in trailing avian migratory cranial NC than in the leading
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migratory NC in vivo (McLennan et al., 2012), suggesting cell-cell adhesion may be
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more important for following rather than leading cells. Using transfected cell lines,
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cadherin 7 has been shown to have higher adhesivity compared to cadherin 11, and
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both type II cadherins have much lower adhesivity compared to N-cadherin (Chu et
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al., 2006).
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N-cadherin is expressed by chick placodal cells but not cranial NC during the
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aggregation of cranial sensory ganglia (Shiau and Bronner-Fraser, 2009). Blocking
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N-cadherin translation in trigeminal placode cells with morpholinos in ovo led to
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misshapen ganglia and decreased aggregation of the placode cells (Shiau and
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Bronner-Fraser, 2009). The cell-surface expression of N-cadherin on placode cells
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was regulated post-translationally by cranial NC-mediated Slit1 activation of Robo2
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expressed by placode cells (Shiau and Bronner-Fraser, 2009).
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Integrins
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Integrins are heterodimeric transmembrane receptors composed of alpha and beta
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subunits, which bind extracellularly to a variety of extracellular matrix molecules and
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other ligands, depending on the combination of subunits (van der Flier and
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Sonnenberg, 2001). Integrins are regulated on many levels; their affinity for ligands
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can be reversibly altered by conformational changes, which can be mediated by
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intracellular or extracellular factors (Hynes, 2002; Luo et al., 2007). Trafficking of
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integrins and distribution of integrins at the cell membrane can also affect the level of
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cell adhesion (Margadant et al., 2011; Ulrich and Heisenberg, 2009). Furthermore,
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integrin-ligand interactions can result in intracellular changes including activation of
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signal transduction pathways, regulating survival, proliferation and gene expression
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(Hynes, 2002; Margadant et al., 2011).
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Cranial NC express a variety of integrins, some of which are restricted to specific
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axial levels, and some to particular species. The integrins that are expressed by
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migrating cranial NC in multiple species are the E1 (Bronner-Fraser, 1985; Gawantka
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et al., 1992; Krotoski and Bronner-Fraser, 1986; Pietri et al., 2004; Ransom et al.,
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1993) and D5 subunits (Alfandari et al., 2003; Bajanca et al., 2004; Joos et al., 1995;
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Wang and Burke, 1995). Integrin D5E1 mediates migration of cranial NC from
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multiple species on fibronectin in vitro (Alfandari et al., 2003; Kil et al., 1998; Lallier
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and Bronner-Fraser, 1992). Inhibiting the function of E1 integrins in chick in ovo
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resulted in reduced cranial NC migration and an ectopic buildup of NC cells in the
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neural tube (Boucaut et al., 1984; Bronner-Fraser, 1985; 1986). Surprisingly, mouse
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conditional knockout studies of E1 integrin using the Wnt1-Cre line showed migration
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of cranial NC cells to the branchial arches (Turlo et al., 2012), however levels of
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proliferation and apoptosis were not assessed. Moreover, in mice null for fibronectin,
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cranial NC cells also still migrate to the branchial arches, but the number of cranial
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NC cells is reduced due to increased apoptosis and decreased proliferation (Mittal et
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al., 2010). Similarly, in integrin D5 null mice, apoptosis occurs in NC cells migrating
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to the second branchial arch (Goh et al., 1997; Mittal et al., 2010). This suggests that
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fibronectin and integrin D5 are critical for the survival of cranial NC, rather than
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migration. Furthermore, the restricted regional effect of loss of D5 suggests that there
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is compensation by other integrins rostral to the second arch. Indeed, integrin D4 is a
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candidate whose expression is restricted to NC rostral to the second branchial arch
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(Pinco et al., 2001). Exposure to D4 function-blocking antibodies in mouse cultures
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inhibited cranial NC migration (Kil et al., 1998), however at least some cranial NC
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migration is normal in D4 null mice, as the trigeminal ganglia are present (Yang et al.,
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1995). In contrast to the axially restricted expression of D4 in mouse, chick cranial
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NC express D4 at all axial levels (Kil et al., 1998), while Xenopus cranial NC do not
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appear to express D4 (Whittaker and Desimone, 1998). The expression of E3, D6 and
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Dv by cranial NC also shows species differences (Alfandari et al., 2003; Joos et al.,
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1998; Lallier et al., 1996; Pietri et al., 2003; Ransom et al., 1993; Wang and Burke,
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1995), but the significance of these differences is not yet clear.
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While it may be surprising that loss of fibronectin or E1 integrin in mice does not
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appear to prevent cranial NC migration, many other extracellular matrix molecules are
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present within the cranial pathway. Chick cranial and trunk NC regulated surface
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integrin expression, location and activity in different ways in response to different
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concentrations and types of extracellular matrix substrates in vitro.
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concentrations of laminin, cranial NC migrated faster than trunk NC (Strachan and
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Condic, 2003), by modulating surface integrin expression in a manner involving
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integrin receptor recycling (Strachan and Condic, 2004). In contrast, on fibronectin,
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receptor recycling did not occur (Strachan and Condic, 2004). Cranial NC reduced
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surface expression of D4 integrin on high concentrations of fibronectin, whereas trunk
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NC did not (Strachan and Condic, 2003). Migration on fibronectin was regulated by
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the activation of integrins, and interestingly cranial and trunk NC responded to
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integrin activation in different ways depending on the concentration of the fibronectin
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substrate (Strachan and Condic, 2008). Integrin activation of cranial NC on low
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concentrations of fibronectin increased avidity (integrin clustering), and on high
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concentrations of fibronectin increased affinity (Strachan and Condic, 2008).
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On high
In
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contrast, in trunk NC, integrin activation on low concentrations of fibronectin
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increased affinity, and on high concentrations of fibronectin increased avidity. In
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each of these cases, integrin activation slowed migration on fibronectin, but not on
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laminin (Strachan and Condic, 2008). These differences highlight the complexity of
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integrin function and regulation, and demonstrate that the NC are capable not only of
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regulation of integrin activity in response to the extracellular environment, but also
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that NC at different axial levels have different responses and regulate integrin
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function and activity differently.
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Matrix Metalloproteases
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Matrix metalloproteases (MMPs and members of the ADAM family) cleave a variety
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of proteins, including extracellular matrix molecules, and cell surface molecules such
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as cadherins, integrins and IgCAMs (Edwards et al., 2008; VanSaun and Matrisian,
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2006). The proteolysis of cell adhesion molecules can disrupt cell-cell adhesion and
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also release soluble extracellular or intracellular fragments that can have further
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signaling effects (Edwards et al., 2008; VanSaun and Matrisian, 2006). In addition,
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ADAMs contain a disintegrin loop which interacts with integrins to influence cell
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adhesion and migration (Huang et al., 2005), and the cytoplasmic domain of ADAMs
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can interact with a variety of proteins to affect catalytic activity, trafficking and cell
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signaling events (Edwards et al., 2008). MMPs and ADAMs have been implicated in
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regulating NC EMT and migration. ADAM13 and 19 are expressed in Xenopus
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cranial NC prior to migration, and early knockdown using morpholinos to ADAM13
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(in Xenopus tropicalis, but not Xenopus laevis), or ADAM19, reduces the expression
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of cranial NC markers (Cousin et al., 2011; Neuner et al., 2009; Wei et al., 2010), and
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inhibits NC migration (Cousin et al., 2011; Neuner et al., 2009). Moreover, knocking
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down ADAM13 and 19 together inhibited NC migration to a greater extent than
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knockdown of either gene alone (Cousin et al., 2011), suggesting that although they
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have some distinct functions during NC development, there is also some
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compensation between these genes (Cousin et al., 2011; Wei et al., 2010).
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ADAM13 continues to be expressed by cranial NC during migration in Xenopus
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(Alfandari et al., 1997) and is expressed in chick cranial NC pathways (Lin et al.,
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2007). ADAM33 is also expressed by migrating avian cranial NC (McLennan et al.,
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2012), and ADAM9 and ADAM11 by Xenopus cranial NC (Cai et al., 1998).
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Multiple ADAMs (ADAM10, 12, 15, 17, 19 and 33) are expressed by cranial NC or
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along the cranial NC migratory pathway in developing mouse embryos (Tomczuk,
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2004). Blocking metalloprotease activity inhibited mouse cranial NC migration on
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fibronectin (Tomczuk, 2004); however the role of specific ADAMs or MMPs during
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mouse cranial NC migration is not yet known.
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ADAM13 in Xenopus in vivo resulted in a large mass of NC cells near the neural tube
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(Alfandari et al., 2001). Expression of a protease defective ADAM13, which acts as a
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dominant negative, reduced migration of NC in the second and more caudal branchial
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arch streams (Alfandari et al., 2001), a similar phenotype to the knockdown of
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cadherin-11 (Kashef et al., 2009). Co-immunoprecipitation and Western blotting
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demonstrated that ADAM13 or ADAM9 cleaves cadherin-11, and inhibiting ADAM
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activity blocks cleavage of cadherin-11 in vivo (McCusker et al., 2009). Moreover,
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increased expression of ADAM13 can rescue the inhibition of NC migration caused
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by an over-expression of cadherin-11 (McCusker et al., 2009); demonstrating that
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ADAM13 mediated cleavage of cadherin-11 is required for normal cranial NC
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migration. Cleavage of the extracellular domain of cadherin-11 in Xenopus cranial
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NC by ADAM13 reduces cell-cell adhesion directly, and the cleaved domain is then
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able to bind to other full-length cadherin-11 molecules, further reducing cell-cell
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adhesion and promoting migration (McCusker et al., 2009).
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cadherin-11 by morpholino is not sufficient alone to rescue a loss of ADAM13 in vivo
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(Cousin et al., 2012), demonstrating that ADAM13 has multiple functions in
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mediating the migration of cranial NC. ADAM13 can also cleave fibronectin, and by
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binding to fibronectin domains, promotes cell adhesion via E1 integrins (Gaultier et
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al., 2002). Manual separation of the cranial NC from the ectoderm and mesoderm in
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vivo partially rescues the loss of ADAM13 (Cousin et al., 2012), suggesting that
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cleavage or modification of extracellular matrix is important in allowing NC
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migration. Moreover, the loss of ADAM13 alone or both ADAM13 and ADAM19
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together did not affect the migration of cranial NC in vitro. ADAM13 needs to be
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expressed by at least some cranial NC in order to allow normal migration of the
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population, and these data suggest that ADAM13 promotes migration partly by
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modifying the extracellular environment through which the cranial NC migrate
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(Cousin et al., 2012).
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Over-expression of full-length
However, reducing
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ADAM13 lacking the cytoplasmic domain is unable to rescue the inhibition of NC
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migration due to ADAM13 morpholino (Cousin et al., 2011).
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domain regulates function by both interacting with the adaptor protein PACSIN2,
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(Cousin et al., 2000) and by altering the subcellular localisation or activity of the
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protease domain after cleavage (Cousin et al., 2011). Cleavage of the cytoplasmic
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domain by J-secretase during NC development allows the translocation of the
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cytoplasmic domain to the nucleus, altering the expression of multiple genes
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including Calpain8-a, a member of a protease family linked to cell migration (Cousin
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et al., 2011). Expression of both the extracellular domain of cadherin-11 combined
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with the cytoplasmic domain of ADAM13 is sufficient to rescue a loss of migration
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caused by combined ADAM13 and ADAM19 morpholino in vivo (Cousin et al.,
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2012).
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multiple mechanisms; both extracellular cleavage of molecules, and regulation of
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transcription via its cytoplasmic domain.
The cytoplasmic
Therefore, ADAM13 promotes Xenopus cranial NC migration through
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Expression or function of ADAMs in particular subsets or stages of NC migration
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may influence the ability of NC cells to migrate to particular regions. For example,
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ADAM10 cleavage of a splice variant of the cell adhesion molecule CD44, CD44v6,
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appears to facilitate migration of NC into the cornea in chick embryos (Huh et al.,
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2007).
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MMP9 is expressed by avian NC cells during EMT and migration, and also by some
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surrounding cells (Monsonego-Ornan et al., 2012). Inhibition of MMP9 activity
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reduces the number of cells emigrating from the neural tube at cranial levels, while
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overexpression, or MMP9 conditioned media, increases the number of migratory
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cranial NC in vitro and in vivo (Monsonego-Ornan et al., 2012). Thus MMP9 has a
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role in the onset of migration, possibly through degradation of the laminin basement
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membrane. Later inhibition of MMP9 in neural tube explants reduced the distance
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migrated by NC cells on the substrate, while MMP9 conditioned media significantly
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increased the number of emigrating cranial NC (Monsonego-Ornan et al., 2012).
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Migrating NC cells in these explants also demonstrated perturbations in the
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organization of stress fibres, and rapid loss of N-cadherin expression, suggesting N-
11
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cadherin may also be a substrate of MMP9. In contrast to the phenotype in chick,
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MMP9 knockout mice do not display overt embryonic defects (Vu et al., 1998),
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perhaps due to redundancy with other members of the MMP family. MMP2, which is
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closely related to MMP9, is expressed by, or along, the cranial NC migratory pathway
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in chick, mouse and Xenopus, with some differences in expression between species
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(Cai et al., 2000; Robbins et al., 1999; Tomlinson et al., 2009). MMP2 in avian
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cranial NC is expressed at higher levels in leading compared to trailing cells
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(McLennan et al., 2012). In addition, MMP8 is expressed in mouse cranial NC
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(Giambernardi et al., 2001), and MMP14 in a subset of Xenopus NC migrating from
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rhombomeres 3 and 5 (Harrison et al., 2004). However the roles of these MMPs in
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cranial NC migration have not been determined.
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IgCAMs
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Members of the IgCAM family interact extracellularly either homophilically or with
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other proteins, and can exist as multiple isoforms due to alternative splicing.
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IgCAMs interact with numerous intracellular binding partners, ranging from effectors
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of signal-transduction pathways to cytoskeletal proteins.
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cranial NC cells in the chick prior to and in the early stages of migration (Bronner-
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Fraser et al., 1992b). NCAM mediated cell-cell adhesion is important for emigration
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and early stages of cranial NC migration, but is not necessary once migration is
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underway (Bronner-Fraser et al., 1992b). In Xenopus, NCAM is also expressed by
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cranial NC prior to migration, and later during aggregation of cranial ganglia, but is
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not expressed during NC migration (Balak et al., 1987).
NCAM is detected on
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Neuropilins and plexins can in some circumstances be involved in cell adhesion,
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however during NC migration they are best understood for their role in acting as
393
receptors for the Ig domain containing Semaphorin molecules, which often act as
394
chemorepellants or chemoattractants in the guidance of neural crest at multiple axial
395
levels (reviewed in Schwarz and Ruhrberg, 2010). No other IgCAMs are known to
396
play a role in the migration of cranial NC.
397
398
399
12
400
Vagal Neural Crest
401
402
Vagal NC cells, which arise adjacent to somites 1-7, include the most caudal cranial
403
NC cells and the most rostral trunk NC cells. Vagal NC cells give rise to two distinct
404
populations of cells, cardiac NC and enteric NC cells.
405
406
Cardiac NC Cells
407
408
Cardiac NC cells, which arise adjacent to somites 1-3, migrate beneath the ectoderm
409
into branchial arches 3, 4, and 6, where they contribute to the great arteries, the
410
aorticopulmonary septum, the conotruncal cushions in the outflow tract and cardiac
411
ganglia of the developing heart (Kirby and Waldo, 1995; Waldo et al., 1998). Defects
412
in cardiac NC migration result in severe cardiac defects involving outflow tract
413
septation anomalies, such as persistent truncus arteriosus as well as various aortic arch
414
anomalies (Kirby and Hutson, 2010). A number of cell adhesion molecules, including
415
cadherins and integrins, as well as the proteolytic enzymes that cleave them, MMPs
416
and ADAMs, play a role in cardiac NC migration and formation of the developing
417
heart.
418
419
Cadherins
420
421
Cardiac NC cells express cadherin-6, cadherin-7 and caherin-11, as they migrate to
422
the heart. Avian cadherin-6B is expressed at the beginning of migration but is then
423
rapidly down-regulated, while avian cadherin-7 and murine cadherin-6 and murine
424
and Xenopus cadherin-11 are expressed throughout migration (Inoue et al., 1997;
425
Kimura et al., 1995; Nakagawa and Takeichi, 1995; Vallin et al., 1998). Over-
426
expression of these cadherins prevents NC emigration from the neural tube, while
427
down regulation of cadherin-6B results in premature NC emigration (Coles et al.,
428
2007; McCusker et al., 2009; Nakagawa and Takeichi, 1998).
429
430
The main cadherin involved in cardiac NC migration appears to be N-cadherin.
431
Murine N-cadherin is weakly expressed during cardiac NC migration in vitro (Xu et
432
al., 2001) and at regions of cell-cell contact by cardiac NC arriving at their destination
433
in vivo (Luo et al., 2006).
N-cadherin is dramatically up-regulated as the cells
13
434
condense in the outflow tract, and is required for the remodeling of the cardiac
435
outflow tract (Luo et al., 2006). In the absence of N-cadherin, mouse cardiac NC
436
cells migrate faster in vitro, but exhibit a loss of directionality resulting in an overall
437
decrease in the distance migrated (Xu et al., 2001). Despite this, cardiac NC cells
438
from N-cadherin deficient mice do reach the cardiac outflow tract, but are unable to
439
undergo the normal morphogenetic changes, resulting in persistent truncus arteriosus,
440
and in a thinning of the ventricular myocardium (Luo et al., 2006).
441
442
Connexin 43 (Cx43D1) also plays a role in cardiac NC migration by interacting with
443
N-cadherin (Xu et al., 2001) and mediating interactions with signaling pathways that
444
regulate polarized cell movement (Xu et al., 2006). In N-cadherin deficient mice,
445
cardiac NC cells display a reduced level of gap junction communication that is similar
446
to Cx43D1 deficient NC cells (Xu et al., 2001). Cx43D1 deficient mice die at birth
447
due to severe pulmonary outflow tract obstruction (Reaume et al., 1995). Loss of
448
Cx43D1 inhibits cardiac NC cell migration, resulting in fewer cells reaching the
449
outflow tract, while over-expression of Cx43D1 enhanced migration, resulting in
450
more cardiac NC cells reaching the outflow tract (Huang et al., 1998). Like N-
451
cadherin deficient cells, Cx43D1 deficient cardiac NC cells also show reduced
452
directionality (Xu et al., 2001). Interactions between N-cadherin and Cx43D1 may be
453
modulated through p120-catenin signaling (Xu et al., 2001). Although Cx43D1 forms
454
gap junctions, cell-cell communication via gap junctions does not appear to modulate
455
cardiac NC motility (Xu et al., 2006). Instead, Cx43D1 co-localises with many actin
456
binding proteins and is hypothesized to play an important role in regulating the actin
457
cytoskeleton during migration (Xu et al., 2006).
458
459
Integrins
460
Cardiac NC cells in Aves express multiple integrins, including the Dand D subunits
461
(Kil et al., 1998; Wang and Burke, 1995). The D5 and E1 subunits have also been
462
detected in mice (Goh et al., 1997; Xu et al., 2006), and murine cardiac NC synthesise
463
fibronectin as they migrate (Mittal et al., 2010). In D5 integrin null or conditional
464
fibronectin null mutant mice, migration of cardiac NC cells to the heart still occurs
465
(Goh et al., 1997; Mittal et al., 2010), but there is a reduction in the number of cardiac
14
466
NC and increased apoptosis, suggesting that, like more rostral cranial NC, D5 integrin
467
and fibronectin are required for the proliferation of cardiac NC progenitors, and
468
proliferation and survival of cardiac NC during migration (Mittal et al., 2010).
469
470
1 integrins are up-regulated as avian cardiac NC cells emigrate from the neural tube
471
in vivo (Duband et al., 1986). Exposure to 1 integrin function blocking antibodies
472
results in a reduction in the overall speed and directionality of mouse cardiac NC cells
473
in vitro (Xu et al., 2006). Although there are no detectable defects in cardiac NC
474
migration in conditional Wnt1-Cre E1 integrin null mice, cardiac NC did not undergo
475
vascular remodeling, resulting in embryonic lethality (Turlo et al., 2012). Similar
476
cardiac defects and early death are also observed in mice where E1 integrins are
477
eliminated prior to NC emigration from the neural tube (Pietri et al., 2004).
478
479
MMPs
480
481
In order for cardiac NC cells to migrate through the extracellular matrix, they require
482
the proteolytic activity of MMPs and/or ADAMs. Migrating avian cardiac NC cells
483
express MMP2, MMP14 and tissue inhibitor of metalloproteinase (TIMP)-2
484
(Cantemir et al., 2004). Similarly to MMP2 at cranial levels, TIMP-2 is expressed at
485
higher levels in leading compared to trailing cells (Cantemir et al., 2004). Use of anti-
486
sense TIMP-2 oligonucleotides in chick resulted in perturbed cardiac NC formation
487
and decreased NC cell migration away from the neural tube in ovo, while over-
488
expression of TIMP-2 increased cardiac neural cell motility in vitro (Cantemir et al.,
489
2004). TIMP-2 is required for activation of proMMP-2 by MMP14 (Cantemir et al.,
490
2004). MMP-2 is expressed by avian cardiac NC in vitro (Cantemir et al., 2004), and
491
within the substrate through which cardiac NC cells migrate in vivo (Cai et al., 2000).
492
Pharmacological inhibition of MMP-2 in Aves decreases the distance cardiac NC
493
cells migrate in vitro and in vivo, decreases motility and increases cell area and cell
494
perimeter (Cai and Brauer, 2002). However, the migration of cardiac NC cells is not
495
affected in MMP-2 or TIMP-2 null mutant mice (Caterina et al., 2000), suggesting
496
that MMP-2 and TIMP-2 are either not involved in cardiac NC migration in mice in
497
vivo, or that there is functional redundancy with other matrix metalloproteases.
498
15
499
Cardiac NC cells also express ADAM19 in mice (Komatsu et al., 2007), ADAM13 in
500
chick (Lin et al., 2007) and ADAM9, ADAM11 and ADAM13 in Xenopus (Alfandari
501
et al., 2001; Cai et al., 1998). The migration of cardiac NC cells is unaffected in
502
ADAM19-deficient mice (Komatsu et al., 2007).
503
cardiac NC cells are unable to fuse the left and right ridges of the endocardial cushion,
504
resulting in defects in the outflow tract and formation of the ventricular septum
505
(Komatsu et al., 2007).
However, ADAM19-deficient
506
507
Enteric NC Cells
508
509
Enteric NC-derived cells arise from two levels of the neural tube.
The largest
510
contribution of cells originates from the vagal level (adjacent to somites 1-7) (Le
511
Douarin and Teillet, 1973; Yntema and Hammond, 1954), which overlaps with the
512
region that gives rise to cardiac NC. A second, smaller, population of cells originates
513
from the sacral level (caudal to somite 28) and contributes some neurons to the colon
514
in chick and mouse (Anderson et al., 2006a; Burns and Le Douarin, 1998; Kapur,
515
2000; Wang et al., 2011). Defects in vagal NC migration result in variable lengths of
516
the distal gastrointestinal tract lacking enteric neurons; a condition in humans called
517
Hirschsprung disease (HSCR) or congenital aganglionosis. Most of the expression
518
and functional studies of cell adhesion in enteric NC have been carried out using
519
mice, with some data also available from Aves.
520
521
Cadherins
522
523
Enteric NC cells in mice express N-cadherin, Cadherin-11, Cadherin 9 and Cadherin-
524
6 as well as Protocadherins D1, D4, D10 and 15 (Breau et al., 2006; Heanue and
525
Pachnis, 2006; Vohra et al., 2006). Mice null for protocadherin 15 do not display any
526
defects in the structure of the enteric nervous system (Vohra et al., 2006). In contrast
527
to the early down regulation of Cadherin 6B observed in avian vagal NC cells
528
(Nakagawa and Takeichi, 1995), murine Cadherin-6 expression is maintained in
529
enteric NC cells as they colonise the entire length of the gut (Breau et al., 2006).
530
Mouse and avian enteric NC express N-cadherin at low levels during migration,
531
which is up-regulated during aggregation into ganglia (Hackett-Jones et al., 2011).
16
532
Conditional loss of N-cadherin in NC in Ht-PA-Cre mice results in a transient delay in
533
colonization of the gut, with mutant enteric NC exhibiting perturbed directionality
534
compared to control enteric NC and loss of the normal chain-like pattern of migration
535
(Broders-Bondon et al., 2012). However, the delayed migration did not result in
536
intestinal aganglionosis in the mutant mice. Double conditional mouse knockouts of
537
N-cadherin and E1 integrin resulted in a more severe phenotype and intestinal
538
aganglionosis (see below).
539
540
Integrins
541
542
Enteric murine and rat NC cells express several integrins, including the 4, 5, 6,
543
v, 1, E3 and E5 subunits (Bixby et al., 2002; Breau et al., 2009; Breau et al., 2006;
544
Iwashita et al., 2003). The migration of enteric NC cells is impaired in 1 integrin
545
conditional null mutant mice, resulting in absence of enteric ganglia from the distal
546
colon (Breau et al., 2006; Pietri et al., 2003). The absence of 1 integrin also results
547
in an abnormal organization of the enteric ganglia network (Breau et al., 2006; Pietri
548
et al., 2003), with larger aggregations and more space between ganglia. Time-lapse
549
imaging analysis revealed that enteric NC cells lacking 1 integrin migrated more
550
slowly and with less persistence than control cells, most notably around the time of
551
invasion of the caecum and hindgut (Breau et al., 2009). Fibronectin and tenascin-C
552
are expressed at high levels in the caecum and proximal hindgut relative to the
553
midgut. In vitro assays demonstrated that tenascin-C inhibited both adhesion and
554
migration of enteric NC, with a stronger effect on E1 integrin null cells. In contrast,
555
fibronectin stimulated adhesion and migration of control enteric NC, but not integrin
556
E1-null cells. Thus E1 integrins appear to be necessary for fibronectin-mediated
557
migration in the caecum and proximal hindgut, and to overcome the tenascin-C
558
mediated inhibition of migration in these regions (Breau et al., 2009).
559
560
Double conditional mouse knockout of E1 integrin and N-cadherin caused a more
561
severe intestinal aganglionosis than the single E1 integrin mutation, suggesting there
562
is co-operation between these two adhesion molecules during enteric NC migration
563
(Broders-Bondon et al., 2012). However, the abnormal ganglia network observed in
564
E1 integrin mutants was partially rescued in these double mutants. Therefore, the
17
565
organization of the network of enteric ganglia requires a balance of cell-adhesion and
566
extracellular matrix adhesion, modulated by the activity of N-cadherin and E1
567
integrins.
568
569
Integrin E1 is also involved in the migration of chick enteric NC along endothelial
570
cells (Nagy et al., 2009). In chick and zebrafish, there is contact between enteric NC
571
and blood vessels along the gut (Nagy et al., 2009). Pharmacological inhibition of
572
endothelial cell development in cultured avian gut resulted in cessation of enteric NC
573
migration and distal aganglionosis. However, there may be a species difference in
574
this pattern of migration: although enteric NC are reported to be adjacent to blood
575
vessels in chick, in mice they are not co-localised (Young et al., 2004).
576
577
The integrin 2-like gene and integrin DE1 are also expressed by murine enteric NC
578
cells (Iwashita et al., 2003; Vohra et al., 2006), but their role in migration is not yet
579
known.
580
581
MMPs
582
583
Enteric NC cells migrate in chains (Young et al., 2004). However, in order to
584
advance, the cells must transiently weaken adhesion to other enteric NC cells. MMP2
585
(Anderson et al., 2006b), ADAM17 and ADAMTS1 (Iwashita et al., 2003) are all
586
expressed by mouse enteric NC. The expression of MMPs by enteric NC-derived
587
cells permits individual migrating cells to break away from chains (Anderson et al.,
588
2006b). Broad spectum inhibitors to gelatinases MMP 2 and 9 retarded enteric NC
589
migration in explants of mouse gut, as did a specific MMP2 inhibitor (Anderson,
590
2010). Furthermore, the topography of the network was different in that fewer,
591
thicker chains were present following inhibition of MMP2 and 9.
592
593
IgCAMs
594
595
NCAM is expressed by all enteric NC cells in mice (Heanue and Pachnis, 2006;
596
Vohra et al., 2006) and Aves, and expression of NCAM increases following neuronal
597
differentiation (Hackett-Jones et al., 2011). PSA modification of NCAM regulates
18
598
nerve fibre fasciculation and is involved in the clustering of individual enteric NC
599
cells into enteric ganglia. Excessive PSA modification induced by exposure to BMP4
600
reduced the distance migrated by mouse NC cells in gut organ culture (Fu et al.,
601
2006).
602
603
Like NCAM, L1CAM is also expressed by most enteric NC cells in mice (Anderson
604
et al., 2006b) and in Aves by all enteric NC at the wavefront (Hackett-Jones et al.,
605
2011; Nagy et al., 2012). Perturbation studies, using function blocking antibodies and
606
recombinant protein, showed that disrupting L1 activity delays enteric NC cell
607
migration and increases the presence of solitary NC cells close to the migratory
608
wavefront within explants of mouse gut (Anderson et al., 2006b). The migration of
609
enteric NC cells within the developing gut is also delayed in L1cam deficient mice,
610
although no change in the number of solitary cells was reported (Anderson et al.,
611
2006b). Subsequently L1cam has been shown to act as a modifier gene for three
612
HSCR associated genes, Sox10, Et3 and Ednrb, in mice, as interactions between these
613
genes result in a significant increase in the penetrance and/or severity of intestinal
614
aganglionosis in mutant mice (Wallace et al., 2010; Wallace et al., 2011). L1CAM
615
can be cleaved by ADAM10 and ADAM17, which may regulate L1-dependent cell
616
adhesion (Maretzky et al., 2005), and while both L1CAM and ADAM17 are
617
expressed by enteric NC in mice, it is not yet known if this occurs during enteric NC
618
migration.
619
620
Trunk Neural Crest
621
622
Trunk NC cells give rise to neurons and glia in dorsal root ganglia and sympathetic
623
ganglia, Schwann cells, boundary cap cells, cells of the adrenal medulla and
624
melanocytes (Le Douarin and Kalcheim, 1999; Serbedzija et al., 1994; Weston, 1963).
625
Time lapse imaging of migrating trunk NC cells in chick embryos has revealed that
626
they maintain close, extensive and dynamic contact with other NC cells and many
627
migrate in chains through the somites (Kasemeier-Kulesa et al., 2005).
628
629
630
631
19
632
Cadherins
633
634
Both N-cadherin and cadherin 6B have been shown to be involved in avian trunk NC
635
EMT, with quite different roles. Cadherin 6B is expressed in premigratory NC and
636
during EMT, but is absent in NC migrating away from the neural tube similarly to
637
other axial levels (Nakagawa and Takeichi, 1995; Park and Gumbiner, 2010).
638
Inhibition or knockdown of cadherin 6B in avian trunk NC caused a decrease in
639
migrating NC cells, while overexpression increased the number of cells ectopically
640
localised in the neural tube lumen (Park and Gumbiner, 2010). This effect of cadherin
641
6B in the de-epithelialization of the trunk NC is mediated by non-canonical BMP
642
signaling via the BMP type II receptor, involving LIM kinase 1 which phosphorylates
643
cofilin to regulate actin dynamics (Park and Gumbiner, 2012). While overexpression
644
of cadherin 6B at both cranial and trunk levels promoted the ectopic localization of
645
NC cells in the neural tube lumen, inhibition or knockdown had opposing effects on
646
NC EMT. This may be due to differences in methodology, or may reflect inherent
647
differences between cranial and trunk NC, similarly to the requirement for G1-S cell
648
cycle transition, which is necessary for trunk but not cranial NC EMT (Burstyn-
649
Cohen et al., 2004; Theveneau et al., 2007).
650
651
N-cadherin mRNA is expressed in the chick dorsal neural tube prior to and at the time
652
of neural crest migration (Shoval et al., 2007). Overexpression many hours prior to
653
NC emigration in ovo of full-length N-cadherin, but not dominant-negative forms,
654
causes inhibition of trunk EMT (Shoval et al., 2007). N-cadherin can be cleaved by
655
ADAM10, and a second cleavage step intracellularly yields a soluble cytoplasmic tail
656
termed CTF2, which increases cytosolic E-catenin and translocates to the nucleus to
657
regulate gene expression (Reiss et al., 2005). Blocking the action of ADAM10 in
658
vitro inhibits chick trunk NC EMT, which can be rescued by transfection of CTF2
659
(Shoval et al., 2007). Electroporation of the CTF2 fragment in ovo increased EMT,
660
and E-catenin and cyclin D1 expression (Shoval et al., 2007). These experiments
661
suggest that during trunk NC EMT ADAM10 and N-cadherin function in cell
662
signaling and regulation of gene transcription through the action of CTF2/E-catenin.
663
Consistent with this, E-catenin is localized to the nucleus at the onset of migration in
664
avian trunk NC in vitro, but during migration, it is associated with N-cadherin at
20
However, loss of E-catenin in
665
intercellular contacts (de Melker et al., 2004).
666
premigratory neural crest in Wnt1-cre mice does not inhibit NC EMT, but NC-derived
667
melanocytes and dorsal root ganglia fail to develop, suggesting involvement of E-
668
catenin signaling in differentiation of specific lineages rather than EMT or migration
669
(Hari et al., 2002). Interestingly, overstimulation of E-catenin in avian trunk NC in
670
vitro promoted translocation to the nucleus and inhibited EMT and NC migration, by
671
decreasing integrin-mediated cell-matrix adhesion and reduced proliferation (de
672
Melker et al., 2004), showing cross-talk between the actions of different cell adhesion
673
and signaling pathways.
674
675
In contrast to enteric NC, N-cadherin protein does not appear to be expressed during
676
avian trunk NC migration in vivo; expression of N-cadherin is later observed after
677
cells coalesce to form dorsal root and sympathetic ganglia (Akitaya and Bronner-
678
Fraser, 1992; Duband et al., 1988). However, during migration in vitro, avian trunk
679
NC cells retain N-cadherin expression, although it is constitutively phosphorylated
680
and is not associated with the cytoskeleton, such that N-cadherin mediated cell-cell
681
contacts are not stable (Monier-Gavelle and Duband, 1995).
682
location of N-cadherin and stability of N-cadherin mediated cell-cell interactions were
683
modified by the activity or inhibition of protein kinases and phosphatases, but the
684
phosphorylation of N-cadherin was not affected by these protein kinases and
685
phosphatases (Monier-Gavelle and Duband, 1995). Moreover, the localisation of N-
686
cadherin in migrating avian NC in vitro is regulated by E1 and E3 integrin signalling
687
(Monier-Gavelle and Duband, 1997).
688
adhesion increased N-cadherin mediated intercellular adhesion in vitro (de Melker et
689
al., 2004).
690
mRNA. Recent in vivo studies showed that NC cells over-expressing full-length N-
691
cadherin migrated more slowly, as did NC cells expressing a dominant-negative,
692
catenin-binding domain (Kasemeier-Kulesa et al., 2006). These N-cadherin over-
693
expressing NC cells also displayed altered morphology: increased levels of N-
694
cadherin increased the number of filopodia, while those expressing dominant-negative
695
N-cadherin had fewer filopodia. However, the N-cadherin over-expressing NC cells
696
were still able to migrate ventrally to the sympathetic ganglia (Kasemeier-Kulesa et
697
al., 2006).
The intracellular
Decreasing integrin-mediated cell-matrix
It is not yet known if migrating trunk NC in vivo express N-cadherin
In contrast, N-cadherin expressing sarcoma cells failed to migrate
21
698
following transplantation into the avian trunk NC pathway in ovo, in contrast to the
699
parental cell line and cadherin 7 expressing cells (Dufour et al., 1999).
700
differing observations suggests that in trunk NC, high levels of N-cadherin expression
701
may be regulated such that they do not completely inhibit migration. Furthermore,
702
the similar effect of the full-length and dominant-negative N-cadherin on slowing but
703
not abolishing migration further support the notion that increased or decreased levels
704
of cell-cell adhesion slow neural crest migration, and shows similarities to the slowed
705
migration of mouse enteric NC with a conditional loss of N-cadherin (see above).
These
706
707
Cadherin 6 is expressed in mouse NC cells prior to and during migration (Inoue et al.,
708
1997). In Aves, cadherin 7 is expressed by the majority of trunk NC migrating in the
709
ventral pathway to the sympathetic and dorsal root ganglia, and in the dorsolateral
710
pathway (Nakagawa and Takeichi, 1995; 1998).
711
expression of cadherin 7 in a large subpopulation slows the migration of these cells,
712
keeping them together and helping to mediate cell sorting into discrete locations and
713
cell types (Nakagawa and Takeichi, 1995), however recent observations of cranial NC
714
suggest cadherin 7 is expressed at higher levels in following rather than leading or
715
pioneer cells (McLennan et al., 2012). Over-expression of cadherin 7 inhibited the
716
emigration of some NC cells and caused ectopic localisation in the neural tube, in the
717
same manner as over-expression of N-cadherin or cadherin 6B (Nakagawa and
718
Takeichi, 1998; Park and Gumbiner, 2010), which is likely a general effect of
719
increased cell-cell adhesion. Expression of cadherin 7 by sarcoma cells did not inhibit
720
migration of these cells following transplantation to the avian trunk NC pathway
721
(Dufour et al., 1999). The cell-cell interactions between these cadherin 7-expressing
722
sarcoma cells in vitro were transient and more rapidly turned over than N-cadherin
723
mediated interactions (Dufour et al., 1999). Furthermore, the cadherin 7 and N-
724
cadherin mediated adhesion had different effects on integrin-dependent signaling and
725
consequent behavior of the cells on fibronectin (Dufour et al., 1999). Cadherin 11 is
726
expressed the early migrating trunk avian NC and in the mesenchyme through which
727
the NC migrate (Chalpe et al., 2010). The location of these cadherin 11-positive cells
728
suggests that the most ventrally migrating trunk NC express cadherin 11, and that it is
729
only weakly or not expressed in later migrating NC. As trunk NC aggregate into
730
dorsal root ganglia, they only very weakly express cadherin 11, while the surrounding
731
mesenchyme is strongly positive (Chalpe et al., 2010). Both cadherin 7 and cadherin
22
It has been hypothesised that
732
11 are upregulated in avian trunk NC in vitro in response to Wnt3a, at both mRNA
733
level and protein at cell-cell adhesions (Chalpe et al., 2010), suggesting these
734
adhesion molecules are regulated by Wnt signalling.
735
Xenopus trunk neural crest migrating in the dorsal fin (Vallin et al., 1998), and
736
cadherin 19 is expressed in a subpopulation of trunk NC migrating in the ventral
737
pathway in rat (Takahashi and Osumi, 2005). Overall, many questions remain to be
738
answered on the role of type II cadherins during the migration of trunk NC.
Cadherin 11 is expressed by
739
740
In contrast to the expression of cadherins by NC, truncated cadherin (T-cadherin), an
741
atypical cadherin which lacks cytoplasmic sequences, is expressed in the caudal half
742
of each somite, which trunk NC avoid (Ranscht and Bronner-Fraser, 1991). NC
743
avoidance of the caudal half-somite has been shown to be mediated by semaphorin-
744
neuropilin signaling (Gammill and Roffers-Agarwal, 2010), and a role for T-cadherin
745
in NC migration through the rostral somite has not yet been demonstrated.
746
747
Later expression of N-cadherin is required for the aggregation of NC cells in the chick
748
sympathetic ganglia. Inhibition of N-cadherin in trunk NC by function blocking
749
antibodies or dominant-negative constructs resulted in abnormal elongation and
750
increased size of the sympathetic ganglia, while over-expression of N-cadherin
751
decreased the size of the sympathetic ganglia but not length (Kasemeier-Kulesa et al.,
752
2006). These findings demonstrate the role of N-cadherin in mediating aggregation of
753
the ganglia and consequently ganglia size following migration.
754
755
Integrins
756
757
The importance of integrin signalling in NC migration has been demonstrated by
758
manipulations of a scaffolding protein within the integrin signalling pathway, Nedd9
759
(Aquino et al., 2009). Loss or gain of function of Nedd9 decreased or increased
760
respectively the extent of chick trunk NC migration. The expression and function of
761
integrins in the migration of trunk NC has primarily been studied in cultures of avian
762
trunk NC. These studies have shown that many integrins are expressed by trunk NC
763
in vitro: D1E1, D3E1, D4E1, D5E1, D6E1, D7E1, D8E1, DvE1, DvE3, DvE5, and a E8
764
(Delannet et al., 1994; Desban and Duband, 1997; Kil and Bronner-Fraser, 1996;
23
765
Testaz et al., 1999), however the pattern of expression of most integrins in vivo
766
remains to be determined. The expression of integrins E1, D1, D4, D6 and D7 have,
767
however, been examined in vivo in Aves (Bronner-Fraser et al., 1992a; Duband et al.,
768
1992; Kil and Bronner-Fraser, 1996; Kil et al., 1998; Krotoski et al., 1986; Stepp et
769
al., 1994), and some differences have been observed between expression of integrins
770
in vitro and in vivo. Integrin D1 is expressed weakly in vivo (Duband et al., 1992), but
771
strong expression is reported in vitro (Desban and Duband, 1997). Other integrins
772
show dynamic changes of expression in vivo.
773
subpopulation of migrating trunk NC (Kil and Bronner-Fraser, 1996), while integrin
774
D6 is absent from many cells during migration in vivo (Bronner-Fraser et al., 1992a),
775
and is expressed in vitro by a subpopulation of NC, in which it is mostly cytoplasmic
776
(Bronner-Fraser et al., 1992a; Desban and Duband, 1997). During gangliogenesis,
777
integrin D7 is expressed in the dorsal root ganglia, while D6 is expressed in the
778
sympathetic ganglia (Kil and Bronner-Fraser, 1996). Many integrins appear to be
779
widely distributed over the cell surface of cultured NC; however integrins DvE1, D1
780
and E3 also showed localisation to focal contacts (Delannet et al., 1994; Desban and
781
Duband, 1997; Testaz et al., 1999). The integrins expressed by trunk NC mediate
782
migration on multiple substrates, including fibronectin, laminin and vitronectin, all of
783
which are present along the pathways on which NC migrate in vivo and can support
784
migration in vitro (Duband and Thiery, 1987; Krotoski and Bronner-Fraser, 1990;
785
Newgreen and Thiery, 1980; Rovasio et al., 1983).
Integrin D7 is observed on a
786
787
The function of different integrins in mediating migration of avian trunk NC has been
788
mostly addressed by culturing trunk NC on different substrates and using function-
789
blocking antibodies or antisense oligonucleotides to perturb particular integrins.
790
These experiments have revealed that different integrins regulate specific aspects of
791
cell behaviour: some integrins play a role in mediating migration of the NC on
792
particular substrates, while others are involved in adhesion or spreading of the NC and
793
some do not appear to mediate any of these functions. The integrins implicated in
794
migration include: integrin DvE3 on fibronectin (Testaz et al., 1999), vitronectin
795
(Delannet et al., 1994) and laminin-1 (Desban and Duband, 1997), DvE5 on
796
vitronectin (Delannet et al., 1994), and the E1 integrin subunit can pair with D4, D8 or
797
D3 to mediate migration on fibronectin (Lallier and Bronner-Fraser, 1993; Testaz et
24
798
al., 1999), or with D1 on laminin-1 (Desban and Duband, 1997; Desban et al., 2006;
799
Lallier and Bronner-Fraser, 1993).
800
801
Knocking out D1 or E3 integrins in vivo in mice does not cause an abnormal neural
802
crest migration phenotype (Gardner et al., 1996; Hodivala-Dilke et al., 1999), which
803
may reflect functional redundancy (see below). The roles of D4, D5 and E1 subunits
804
have been complicated by the early embryonic lethality of these knockouts (Fassler
805
and Meyer, 1995; Goh et al., 1997; Yang et al., 1995). Some cells lacking E1 integrin
806
can migrate to NC derivatives in chimaeric E1 null mice or following antisense
807
blocking of E1 in chick (Fassler and Meyer, 1995; Tucker, 2004). However it is
808
possible that these E1 integrin null cells were able to migrate due to the presence of
809
wild-type E1 integrin expressing cells. Ht-PA-Cre conditional E1 null mice show
810
normal trunk NC migration, but these cells still retain a low level of E1 integrin
811
expression during NC migration (Pietri et al., 2004). Wnt1-Cre conditional E1 null
812
mice also showed migration of trunk NC; however the extent of migration and
813
number of migratory cells was not examined (Turlo et al., 2012). Integrins D4 and D5
814
are expressed by mouse trunk NC (Goh et al., 1997; Kil et al., 1998), and in D4 null
815
mice, trunk NC migration and early gangliogenesis appear normal (Yang et al., 1995),
816
however D5 null mice die during trunk NC migration (Goh et al., 1997). To study the
817
importance of D4 or D5 integrins, NC null for either integrin were examined in
818
culture, and also grafted into chick NC pathways. Integrin D5 null NC cells migrated
819
poorly on fibronectin, but well on vitronectin, whereas D4 null cells showed normal
820
migration on fibronectin (Haack and Hynes, 2001). This is in contrast to in vitro
821
studies, which show an inhibition of migration using function blocking antibodies to
822
D4 in chick and mouse (Kil et al., 1998; Testaz and Duband, 2001), and no effect on
823
migration using function blocking antibodies to D5 (Testaz et al., 1999). When
824
grafted into chick embryos, many D4-null glial progenitor cells underwent apoptosis
825
during migration, especially those migrating dorsally, however some were able to
826
migrate and contribute to the peripheral nervous system (Haack and Hynes, 2001).
827
Blocking D4E1 integrin in cultured chick NC also results in a large increase in
828
apoptosis (Testaz and Duband, 2001). Integrin D5 null cells migrate well in chick NC
829
pathways, although the cells did not survive in the glial lineage (Haack and Hynes,
25
830
2001). Although there are some discrepancies in the behavior of null cells compared
831
to function-blocking antibody studies, overall the data suggest that a lack of integrin
832
D5 alone does not impair trunk NC migration and integrin D4 may play a role in
833
mediating NC survival.
834
835
In summary, trunk NC express a wide variety of integrins during migration, and
836
multiple substrates are present along NC pathways in vivo. There is likely to be
837
significant functional redundancy as the loss of single integrin subunits does not
838
reduce migration in vivo, and blocking of multiple integrins is required to completely
839
prevent NC migration on fibronectin: either blocking of both E1 and DvE3, or D3, D4
840
and Dv combined (Testaz et al., 1999). Combined knockdown studies of multiple
841
integrins in vivo, particularly E1 and Dv, may be necessary to gain a greater
842
understanding of the role of integrins during trunk NC migration.
843
complicating the analysis of integrin function is cross-talk that occurs between
844
different integrins, by which integrins can regulate the functioning and expression of
845
other integrins (Retta et al., 2001; Testaz and Duband, 2001). In addition, in vitro
846
work using avian NC demonstrated regulation of integrin activity in response to
847
different extracellular environments (see Cranial Neural Crest section above), with
848
responses differing between cranial and trunk NC (Strachan and Condic, 2003; 2004;
849
2008). Lastly, expression of particular integrin subunits, D4 and D5, may be required
850
for cell survival rather than, or in addition to, mediating migration, highlighting the
851
importance of integrin-mediated signaling during NC development.
Further
852
853
MMPs
854
855
ADAM10 is expressed in the dorsal neural tube in the avian trunk, and in the
856
ectoderm, dermatome and myotome, and in trunk NC in culture (Hall and Erickson,
857
2003). ADAM10 expression in the dorsal neural tube cleaves N-cadherin and plays a
858
role in regulating NC EMT as described above (Shoval et al., 2007); however roles
859
for ADAM family members in regulating trunk NC migration have not been
860
demonstrated.
861
26
862
Multiple MMPs are expressed by migrating trunk NC, including MMP8 in mouse NC
863
(Giambernardi et al., 2001), MMP2 weakly in avian NC (Duong and Erickson, 2004)
864
or Xenopus mesenchyme (Tomlinson et al., 2009), MMP14 in migrating Xenopus NC
865
(Harrison et al., 2004), and MMP9 in avian premigratory and migratory NC
866
(Monsonego-Ornan et al., 2012).
867
differences between species; MMPs may be required for NC EMT in chick but not in
868
Xenopus. Chemical inhibition of MMP activity or knocking down MMP2 in chick by
869
morpholino prior to NC EMT reduced EMT and migration in vitro and in ovo, while
870
knockdown in NC cells just emerging from the neural tube did not inhibit their
871
migration (Duong and Erickson, 2004). Similarly, inhibition of MMP9 or use of
872
MMP9 morpholinos reduced the number of migrating trunk NC, while overexpression
873
or presence of MMP9 conditioned media increased the number of migratory cells and
874
promoted premature EMT of trunk NC in chick in culture and in ovo (Monsonego-
875
Ornan et al., 2012). This effect may be due to degradation of laminin in the basement
876
membrane (Monsonego-Ornan et al., 2012).
877
inhibition of either MMP2 or MMP14 or both in Xenopus perturbed the migration of
878
melanophores, but no effect on EMT was observed, nor was the migration of other
879
NC cells affected (Tomlinson et al., 2009).
The function of these MMPs shows some
In contrast, in vivo knockdown or
880
881
IgCAMs
882
883
NCAM is expressed in the neural tube, and remains in avian trunk NC cells as they
884
undergo EMT and begin to migrate, but is gradually down-regulated during migration
885
(Akitaya and Bronner-Fraser, 1992), before being later upregulated in the ganglia
886
(Duband et al., 1985; Lallier and Bronner-Fraser, 1988; Thiery et al., 1982). Whether
887
NCAM expression during the early phase of trunk NC migration is important is not
888
yet understood. In contrast to the downregulation of NCAM during NC migration,
889
Melanoma Cell Adhesion Molecule (MCAM, also known as gicerin, HEMCAM and
890
CD146) is expressed in migrating avian trunk NC (Alais et al., 2001). MCAM can
891
regulate adhesion by controlling expression of integrins (Alais et al., 2001), and is
892
upregulated during melanoma metastasis (Lehmann et al., 1987; Luca et al., 1993; Xie
893
et al., 1997), but its function in NC migration is unknown.
894
895
27
896
Conclusions
897
898
In summary, the process of cell migration requires interactions between the migrating
899
cells and the surrounding environment, consisting of neighboring cells and
900
extracellular matrix molecules. An optimal level of cell adhesion is required for
901
migration, as too little adhesion does not generate sufficient traction for motility,
902
while too much adhesion will result in the cells remaining stationary. The families of
903
cell adhesion molecules involved in NC migration, cadherins, integrins and the
904
immunoglobulin superfamily, regulate cell-cell and/or cell-matrix adhesion, and are
905
also important components of various cell signaling pathways that affect many
906
aspects of cell behavior including proliferation, cytoskeleton dynamics and gene
907
transcription.
908
intracellularly and extracellularly.
909
regulate the activity, membrane localization and trafficking, and hence cell adhesion
910
function of the adhesion molecules. Furthermore, activity of one family of adhesion
911
molecules can influence the function of other adhesion molecules, such as integrins
912
and cadherins. Extracellularly, cleavage by matrix metalloproteases can affect the
913
function of cell adhesion molecules, not only by reducing the level of adhesion, but
914
also by releasing the adhesion molecule for intracellular signaling functions, such as
915
the cleavage of N-cadherin by ADAM10 during trunk NC EMT. In addition, NC
916
cells can respond to differences in the extracellular environment to which they are
917
exposed by altering their activity, expression and/or localization of adhesion
918
molecules, such as integrins.
919
adhesion molecules during NC migration is complex and multifaceted.
The function of the adhesion molecules can be regulated both
Various intracellular signaling pathways can
Consequently, the regulation and function of cell
920
921
Understanding how NC cells use cell adhesion molecules to migrate has important
922
implications for understanding the etiology of some neurocristopathies, and the
923
mechanisms neural crest-derived cancerous cells may use to migrate during
924
metastasis.
925
numerous cell adhesion molecules during neural crest migration has been elucidated.
926
There are, however, many gaps in our knowledge and understanding of the role of
927
these cell adhesion molecules during the process of migration, particularly in vivo.
Over the past thirty years, the expression pattern and function of
928
28
929
Along the embryonic axis there are differences in the extracellular substrates and
930
pathways available to NC, differences in derivatives formed and even differences in
931
mechanisms of EMT.
932
mechanisms used by the NC to undergo EMT and migrate are likely to reflect this.
933
Some cell adhesion molecules appear to have similar functions at all axial levels, such
934
as MMP9, which, when inhibited in chick embryos causes a reduction in NC
935
migration at both cranial and trunk levels. Other cell adhesion molecules appear to
936
play a role at only one axial level, for example L1CAM, expressed by the enteric NC
937
in mice and chick. Loss or inhibition of L1CAM slows the colonization of the gut by
938
enteric NC in mice. In addition, NC from a single axial level migrate to multiple
939
target sites and give rise to different types of derivatives. Several cell adhesion
940
molecules, such as some integrins and cadherins, appear to be restricted to
941
subpopulations of NC within an axial level, but the function of these differences is not
942
yet clear. Recent data suggest that the level of expression of some integrins and
943
cadherins differs depending on whether the cell is a leading or following cell, that this
944
expression is plastic and likely reflects different mechanisms of migration between
945
leading and following cells (McLennan et al., 2012). There are both differences and
946
similarities in the cell adhesion molecules employed by the NC in different species.
947
Some of these variations may reflect different mechanisms by which NC cells use to
948
migrate in different species. Other variations may reflect different members of a gene
949
family playing a similar role in multiple species.
Therefore, the cell adhesion molecules and molecular
950
951
Many of the studies carried out on NC cells have been conducted in vitro, particularly
952
with the integrins. This was done out of necessity, and these studies have been very
953
informative. However, there are limitations in the application of these results to NC
954
migration in vivo. Another complication to understanding the role of cell adhesion
955
molecules in vivo is functional redundancy or compensation between members of a
956
family, and in the case of integrins, cross talk between integrins expressed by a single
957
cell. These factors can make it very difficult to tease out the role of particular
958
molecules. Applying some of the newer technologies to these questions may provide
959
important insights. For example, the use of knockdown technologies, fluorescent
960
tagging of particular cell adhesion molecules or their intracellular partners, in vivo
961
imaging and other technologies have great potential for advances in this field, to give
29
962
us a much greater understanding of how these cell adhesion molecules function during
963
NC cell migration.
964
965
966
Acknowledgements
967
We thank Prof Heather Young for insightful comments and feedback on the
968
manuscript. SJM was supported by an NHMRC CJ Martin Fellowship (400433), and
969
RBA by an NHMRC CDA Fellowship (454773).
970
971
30
972
973
974
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975
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Highlights
x
x
x
x
Migrating neural crest cells express a variety of cell adhesion molecules
Expression of adhesion molecules can vary between axial levels and species
Cleaving of cell adhesion molecules by matrix metalloproteases can affect
migration
Function of adhesion molecules can be similar or different between axial
levels
42
Vagal
enteri
c
Vagal
cardia
c
6
Cadherin
74
Ncadherin
4,5
Cadheri
n 6B
(EMT)
Cadherin 6
39,40,41,42
43
Cadherin 6 Cadherin
1
6B
(EMT) 4
Cadherin
Cadherin
11 2
74
Ncadherin
(weak) 33
NNcadherin
cadherin
Rodent
Axial
level
of NC
Crani Cadherinal
61
Cadherin11 2
Cadherin19 (rat) 3
Cadherins
Avian
Cadherin
11 34
Cadheri
n-11 8
PCNS 9
146
4 44
5 45
6 42
v 45
v
1 16
3 15
56
15
4 13
5 14
14
4 13
5 14
6
(subset
R6-8)
5 35
1 36
4 10
5 11
1 12
Ncadherin
7
Roden
t
Xenopus
Rodent
ADAM1
7 42
ADAMT
S1 42
5 17
ADAM1
0 21
6
(subset) ADAM1
18
2 21
V
ADAM1
(weak) 5 21
19
ADAM1
7 21
1 20
ADAM1
9 21
ADAM3
3 21
MMP2 22
MMP8 23
ADAM1
9 37
Integrins
Avian Xenopu
s
ADAM11
27
MMP2
25,38
MMP14
TIMP-2 38
28
ADAM13
27
38
ADAM9
24
MMP2 30
MMP14 31
29
ADAM19
28
ADAM13
MMP2
MMP9 26
ADAM13
25
25
ADAM11
6
27
ADAM33
ADAM9
24
Xenopus
ADAM13
MMPs
Avian
NCAM2
40,48
NCAM 39
L1CAM
L1CA
M 43
49
NCAM
32
NCAM
IgCAMs
Rodent
Avian
Xen
opus
Table 1: Expression of the major classes cell adhesion molecules in NC by axial level and species. Underlining or bolding indicates a function
for the molecule during NC migration has been demonstrated in vitro or in vivo respectively.
10
4
1
52
Trunk Cadherin 6 Cadheri
1
n 6B
Cadherin
(EMT) 4,
50
3
19 (rat)
Cadherin
7
(subset) 4
Cadherin
11 51
Ncadherin
(in vitro)
Pcdh 15 41
41
Pcdh
41
Pcdh
40
Pcdh
41
Cadherin
11 39
Cadherin 9
39,41
39
6 11
1 12
11,35
4
(weak
) 13
5
42
3
5 39
2like 41
E1
39,42
1
54,55
8 55
v
5 59
8 54,55
54,55,59
1 60
3
54,55,59
58
3
4 55,56
5 55
6 54,57
7
(subset)
53,54
1
(weak)
MMP2
(weak) 62
MMP9 26
61
MMP8 23 ADAM 10
47
MMP2
(in NC
or
pathway)
MMP14
30
31
MMP2 (in
pathway)
Igsf4a 41
41
NCAM
(downreg) 64
63
MCAM
(Inoue et al., 1997), 2 (Kimura et al., 1995), 3 (Takahashi and Osumi, 2005), 4 (Nakagawa and Takeichi, 1995), 5 (Taneyhill et al., 2007) 6
(McLennan et al., 2012), 7 (Theveneau et al., 2010), 8 (Hadeball et al., 1998; Vallin et al., 1998), 9 (Rangarajan et al., 2006), 10 (Pinco et al.,
2001), 11 (Bajanca et al., 2004), 12 (Pietri et al., 2004), 13 (Kil et al., 1998), 14 (Wang and Burke, 1995), 15 (Pietri et al., 2003), 16 (Bronner-Fraser,
1985; Duband et al., 1986), 17 (Joos et al., 1995), 18 (Lallier et al., 1996), 19 (Joos et al., 1998), 20 (Krotoski and Bronner-Fraser, 1990; Ransom et
al., 1993), 21 (Tomczuk, 2004), 22 (Robbins et al., 1999), 23 (Giambernardi et al., 2001), 24 (Lin et al., 2007), 25 (Cai et al., 2000), 26 (MonsonegoOrnan et al., 2012), 27 (Cai et al., 1998), 28 (Alfandari et al., 1997), 29 (Neuner et al., 2009), 30 (Tomlinson et al., 2009), 31 (Harrison et al., 2004),
32
(Bronner-Fraser et al., 1992b), 33 (Luo et al., 2006; Xu et al., 2001), 34 (Vallin et al., 1998), 35 (Goh et al., 1997), 36 (Xu et al., 2006), 37
(Komatsu et al., 2007), 38 (Cantemir et al., 2004), 39 (Breau et al., 2006), 40 (Heanue and Pachnis, 2006), 41 (Vohra et al., 2006), 42 (Iwashita et
al., 2003), 43 (Hackett-Jones et al., 2011; Nagy et al., 2012), 44 (Bixby et al., 2002), 45 (Breau et al., 2009), 46 (Nagy et al., 2009), 47 (Anderson,
2010), 48 (Anderson et al., 2006b), 49 (Hackett-Jones et al., 2011), 50 (Park and Gumbiner, 2010), 51 (Chalpe et al., 2010), 52 (Monier-Gavelle and
Duband, 1995), 53 (Duband et al., 1992), 54 (Desban and Duband, 1997), 55 (Testaz et al., 1999), 56 (Kil et al., 1998; Stepp et al., 1994), 57
(Bronner-Fraser et al., 1992a), 58 (Kil and Bronner-Fraser, 1996), 59 (Delannet et al., 1994), 60 (Duband et al., 1986; Krotoski et al., 1986), 61
(Hall and Erickson, 2003), 62 (Duong and Erickson, 2004), 63 (Alais et al., 2001), 64 (Akitaya and Bronner-Fraser, 1992)
1