Download Cell-intrinsic drivers of dendrite morphogenesis

© 2013. Published by The Company of Biologists Ltd | Development (2013) 140, 4657-4671 doi:10.1242/dev.087676
REVIEW
Cell-intrinsic drivers of dendrite morphogenesis
Sidharth V. Puram1,2 and Azad Bonni1,2,3,*
KEY WORDS: Cell-intrinsic driver, Dendrite development, Dendrite
morphogenesis, Dendrite patterning, Transcription factor, Ubiquitin
ligases
Introduction
With their tremendous complexity and diversity, dendrites are one
of nature’s architectural masterpieces. More than a century ago,
Ramón y Cajal proposed an important role for dendrites (referred to
at that time as protoplasmic processes) as specialized morphological
structures that receive neuronal input (Ramón y Cajal, 1995).
Further studies using a variety of neuronal cell types (see Glossary,
Box 1) have vastly improved our understanding of dendrite
development (Scott and Luo, 2001; Grueber and Jan, 2004). The
development of new approaches for studying dendrite
morphogenesis (see Box 2) has led to the view that axons and
dendrites work in concert to define neuronal connectivity. A key
concept that has emerged from such functional studies is that the
particular shapes of dendrites are intimately tied to the proper wiring
of neuronal circuits and their function (Häusser et al., 2000; Parrish
et al., 2007b; Branco et al., 2010; Branco and Häusser, 2011; Gidon
and Segev, 2012; Lavzin et al., 2012).
Prior to the elaboration of dendrites, neurons undergo axodendritic polarization, whereby the morphologically and functionally
distinct axonal and dendritic compartments (see Box 3) are
specified. In most neurons, including retinal ganglion neurons,
forebrain pyramidal neurons and cerebellar granule neurons, the
generation of an axon precedes the development and elaboration of
dendrites (Ramón y Cajal, 1995). Although individual neuronal cell
1
Department of Neurobiology, Harvard Medical School, Boston, MA 02115, USA.
Program in Biological and Biomedical Sciences, Harvard Medical School,
Boston, MA 02115, USA. 3Department of Anatomy and Neurobiology, Washington
University School of Medicine, St Louis, MO 63110, USA.
2
Box 1. Glossary
Anterodorsal and lateral projection neurons (aPNs and lPNs). These
neurons of the Drosophila antennal lobe are crucial for olfactory
processing. They receive excitatory input from olfactory receptor neurons
in glomeruli and transmit signals to the mushroom body and lateral horn.
Cerebellar granule neurons. The most numerous neurons of the brain,
these offer an ideal system for biochemical, morphological and
physiological studies. Granule neurons undergo typified stages of
development, which can be studied in dissociated culture, slices and in
vivo. These neurons form specialized structures for synaptic input known
as dendritic claws, which receive inputs from mossy fiber terminals and
Golgi neuron axons.
Cortical pyramidal neurons. These vary in morphology depending on
the layer they occupy, but typically have a multipolar morphology with a
single apical dendrite, multiple basal dendrites and a single axon. Like
granule neurons, cortical neurons can be studied in dissociated culture,
slices and in vivo.
Dendritic arborization (da) neurons. These are lateral periphery
sensory neurons that cover the Drosophila body wall. They have a
typified branching pattern depending on their subtype. Class I da
neurons have the simplest arbors, whereas Class IV have the most
complex dendritic arbors covering larger dendritic fields. Class-specific
variation allows analysis of the factors driving simple and complex
dendritic arbors.
External sensory (ES) neurons. These neurons originate from a single
precursor cell after a series of asymmetrical divisions, ultimately forming
the Drosophila external sensory organ. ES neurons have been used to
analyze the Drosophila peripheral nervous system, and deficits in ES
neurons can be studied in behavioral assays.
γ neurons. These neurons are found in Drosophila mushroom bodies
(structures involved in olfactory memory). During the first day of pupal
life, γ neuron dendrites undergo extensive degeneration with loss of
dendrites branching into the larval vertical and medial lobes. Dendrites
then regrow as adult projection patterns are established.
Hippocampal pyramidal neurons. These neurons have numerous
synaptic inputs and specialized protrusions known as dendritic spines
along their dendrite shafts. They have been used for electrophysiology
and morphology studies, although analyses typically require methods
such as Scholl analysis because of the density of dendrites.
Multidendritic (md) sensory neurons. Also known as type II neurons
of the peripheral nervous system, these are divided into three subtypes:
tracheal dendrite (md-td), bipolar dendrite (md-bd) and dendritic
arborization (da). They are located along the body wall, where they serve
as touch receptors and proprioceptors.
Optic tectal neurons. Xenopus optic tectal neurons receive and
integrate visual as well as auditory, somatosensory and vestibular inputs.
In addition to electrophysiological analyses, these neurons can easily be
labeled and visualized in vivo allowing time-lapse studies of dendrite
morphogenesis.
Retinal ganglion cells (RGCs). These neurons are located in the
ganglion cell layer of the retina, which receives inputs from bipolar and
amacrine cells. The primary output of these cells is to higher order
centers in the brain, such as the thalamus and hypothalamus, as well as
midbrain structures.
Vertical system neurons. These are present in the lobula plate of the
Drosophila optic lobe, where they are responsible for motion detection
and stabilization reflexes during flight. They have a complex and highly
elaborate set of dendrites and an axon that travels medially towards the
esophagus.
*Author for correspondence ([email protected])
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DEVELOPMENT
ABSTRACT
The proper formation and morphogenesis of dendrites is fundamental
to the establishment of neural circuits in the brain. Following cell cycle
exit and migration, neurons undergo organized stages of dendrite
morphogenesis, which include dendritic arbor growth and elaboration
followed by retraction and pruning. Although these developmental
stages were characterized over a century ago, molecular regulators
of dendrite morphogenesis have only recently been defined. In
particular, studies in Drosophila and mammalian neurons have
identified numerous cell-intrinsic drivers of dendrite morphogenesis
that include transcriptional regulators, cytoskeletal and motor
proteins, secretory and endocytic pathways, cell cycle-regulated
ubiquitin ligases, and components of other signaling cascades. Here,
we review cell-intrinsic drivers of dendrite patterning and discuss how
the characterization of such crucial regulators advances our
understanding of normal brain development and pathogenesis of
diverse cognitive disorders.
REVIEW
Development (2013) doi:10.1242/dev.087676
Box 2. Techniques and culture systems for studying
dendrite morphogenesis
types have specific programs of dendrite development, the critical
steps in dendrite morphogenesis can be broadly defined (Fig. 1).
First, dendrites extend away from the soma into their target field
using guidance cues to steer towards or away from their targets.
During this time, dendrites grow and attain length, diameter, growth
rate and molecular characteristics that are distinct from those of
axons (Craig and Banker, 1994). Second, as dendrites grow farther
away from the soma, branching is necessary to cover the target field.
Dendrites can branch numerous times, with extensive secondary and
tertiary branching. Dendrite branching occurs primarily via
interstitial branching, whereby branches emerge from the side of
existing dendrite shafts; branches initially appear as filopodia then
morph into growth cone-like structures and extend to become stable
branches (Dailey and Smith, 1996). Third, dendrite growth is
restrained as the dendrite arbor reaches defined borders, giving rise
to the mature shape of the dendritic tree (Wässle et al., 1981; Gao
et al., 1999). For example, retinal ganglion cells (RGCs, see
Glossary, Box 1) stop growing upon contact with neighboring RGCs
of the same type (Wässle et al., 1981), allowing each functional
group of RGCs to non-redundantly cover the entire retina. Such
dendritic tiling occurs in diverse populations of neurons (Perry and
Linden, 1982; Kramer and Kuwada, 1983; Amthor and Oyster,
1995; Grueber et al., 2002; Sagasti et al., 2005; Millard and
Zipursky, 2008; Huckfeldt et al., 2009) and is induced by repulsive
interactions between dendrites of the same neuron type. In some
systems, dendritic fields may be spatially restricted to a twodimensional plane, thereby facilitating these repulsive contacts (Han
et al., 2012). Self-avoidance ensures that dendritic branches of the
same neuron spread out evenly within a territory (Corty et al., 2009).
In other neurons, such as Drosophila motoneurons, dendrites have
a domain organization that relies on molecular boundaries defined
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Specification
Growth/branching
Pruning
Differentiation
Fig. 1. Critical stages of dendrite morphogenesis in mammalian
neurons. The morphogenesis of granule neuron dendrites in the cerebellar
cortex, like that of dendrites in other areas of the brain and in other
organisms, occurs via distinct stages mediated by a variety of molecular
regulators. After exiting the cell cycle, neural progenitors undergo
polarization, whereby an axon is specified and subsequently extends, and
this is followed by the specification of additional processes as dendrites.
Dendrite morphogenesis then begins with dendrite growth and branching.
Exuberant dendrite arbors are then pruned with the elimination of some
processes but not others, yielding the dendrites that will persist after
development. These remaining dendrites undergo a process of differentiation
and maturation, whereby they develop specialized structures suited to the
formation of synapses and contact with axons. Although the exact order of
these steps and their timing varies between individual neuronal types and
organisms, these fundamental steps are generally conserved. The image
shown depicts granule neurons of the rat cerebellar cortex at distinct stages
of dendrite development as initially drawn and characterized by Ramón y
Cajal (Ramón y Cajal, 1995). In the last stage, specialized structures for
synaptic input known as dendritic claws are pictured as cup-like extensions
at the ends of the dendrites.
during segmentation of the embryo (Landgraf et al., 2003). Together,
these mechanisms of dendritic tiling and self-avoidance are essential
for limiting dendrite growth and establishing non-redundant
coverage of distinct territories. Fourth, dendrites differentiate and
develop specialized structures that house synapses. In hippocampal
pyramidal neurons (see Glossary, Box 1), dendrites generate small
specialized protrusions termed dendritic spines (Peters et al., 1991),
whereas in cerebellar granule neurons (see Glossary, Box 1)
dendrites form cup-like structures termed dendritic claws at their
ends (Palay and Chan-Palay, 1974). These steps in dendrite
patterning are necessary for the accurate formation of neuronal
circuitry. Finally, dendrite pruning is an important step in
establishing the mature dendritic arbor. In Drosophila, dendrites can
undergo substantial remodeling during metamorphosis from larva to
adults. These changes occur through programmed degeneration of
the dendrite arbor, with molecular pathways governing the
fragmentation of dendrites and clearance by phagocytosis (Williams
and Truman, 2005). The soma then undergoes a process whereby a
new dendritic arbor is regrown. By contrast, pruning in mammalian
neurons refers to the modification of arbors via retraction and
elimination of dendrite branches. For example, in the rodent
cerebellum, following the stage of exuberant arbors, dendrites are
DEVELOPMENT
Single-cell labeling in combination with genetic manipulation in several
culture systems and organisms has been used to assess gene function
in neurons. In particular, methods including biolistic transfection
(Karlsgodt et al., 2008), DiI labeling (Arnold et al., 1994; Lo et al., 1994)
and viral transfection (Gan et al., 2000) have facilitated studies of
dendrite development. In addition, expression of genes/markers from
specific promoters has been used to visualize subpopulations of neurons
(Nedivi et al., 1998). Genetic mosaic methods have been used to label
and genetically manipulate individual neurons (Gao et al., 1999;
Holtmaat et al., 2009).
Many studies have been carried out in Drosophila due to the wellcharacterized nature of specific neuron populations, the ability to carry
out forward genetic screens, and the ease of studying unique aspects of
dendrite morphogenesis. C. elegans also offers an elegant system for
genetic studies of proteins involved in dendrite morphogenesis, and
several major findings in the field have originated in nematodes.
However, the characterization of dendrite morphogenesis in specific
neuronal populations in nematodes lags behind that of flies and
mammals. The vast majority of studies in mammalian systems have
been carried out in rodents, including mice and rats, mostly using
cortical, hippocampal or cerebellar granule neurons. All three populations
can be studied in dissociated cultures or using an ex vivo approach with
slice cultures, as well as in vivo using electroporation, viral transduction
or genetic knockouts. Furthermore, behavioral assays in mammalian
systems offer the advantage of studying the complex behaviors and
pathologies seen in humans. However, compared with Drosophila and
C. elegans, characterizing the regulators of dendrite morphogenesis in
mammals and their effects on behavior and neuronal connectivity are
technically more arduous and time consuming. Thus, the combination of
Drosophila, C. elegans and mammalian systems offers a complementary
approach to the study of dendrite morphogenesis.
Box 3. Structurally and functionally defining axons and
dendrites
Neuronal polarization follows a strictly orchestrated and tightly controlled
sequence of events (Lee and Luo, 1999; Barnes and Polleux, 2009), with
distinct axonal and dendritic compartments defined by much more than
their functional differences as the output and input processes,
respectively, of the neuron. Structurally, dendrites are supported by an
intricate scaffold of microtubules and filamentous actin (F-actin).
Microtubules fill the interior of dendrites providing structural integrity,
while F-actin is distributed along the cortex (Tahirovic and Bradke, 2009;
Cáceres et al., 2012). In mammalian neurons, the structural protein Tau1 (also known as Mapt) is typically localized in axons, whereas dendrites
can be identified based on enrichment of microtubule-associated protein
2 (Map2) (Peters et al., 1991). Furthermore, in contrast to axons, which
have unidirectional plus-end-distal microtubules, dendrites have both
plus- and minus-end-distal populations (Baas et al., 1991; Baas and Lin,
2011). Thus, structural as well as functional differences define the distinct
axonal and dendritic compartments in neurons.
pruned to establish their mature shape and subsequently undergo
postsynaptic differentiation (Ramón y Cajal, 1995; Okazawa et al.,
2009). The process of pruning may therefore ensure that only
dendrites that are properly innervated undergo maturation (Wingate
and Thompson, 1994; Wong et al., 2000; Ramos et al., 2007).
The molecular mechanisms regulating dendrite morphogenesis
can be broadly divided into cell-extrinsic and cell-intrinsic
mechanisms. Chemoattractive and chemorepulsive cues, such as
ephrins, semaphorins and neurotrophins, are important examples of
cell-extrinsic regulators of dendrite morphogenesis (Whitford et al.,
2002; Jan and Jan, 2003; Miller and Kaplan, 2003; Kim and Chiba,
2004). Cell-intrinsic control refers to mechanisms that do not strictly
depend on external cues, although external cues may influence their
activity (Goldberg, 2004; Kim and Bonni, 2007; Stegmüller and
Bonni, 2010; Yang et al., 2010; de la Torre-Ubieta and Bonni, 2011;
Puram and Bonni, 2011; Yamada et al., 2013). The cell-extrinsic
regulators of dendrite morphogenesis, including cell surface
receptors and other membrane-bound proteins, have been reviewed
(Scott and Luo, 2001; Whitford et al., 2002; Grueber and Jan, 2004;
Konur and Ghosh, 2005; Corty et al., 2009) and will not be
discussed here. Rather, we focus our attention on the major cellintrinsic mechanisms, namely the regulators operating within the
cell downstream or independently of cell surface receptors and other
neurons, and their role in dendrite morphogenesis in both
invertebrates and mammals. In doing so, we provide a
comprehensive review of dendrite biology, offering insights into
potential areas of future investigation and conveying broader themes
within the field.
The importance of cell-intrinsic control of dendrite
patterning
During development, different neuronal cell types encounter similar
environmental factors. However, intrinsic pathways within each
neuron control the cellular interpretation of these extrinsic cues, thus
allowing neurons to generate distinct patterns of dendrite
development. For example, distinct cortical pyramidal neurons (see
Glossary, Box 1) respond differently to the same neurotrophin:
exposure of cortical slices to neurotrophin 4 (NT-4, or Ntf4) induces
dendrite arborization and complexity in layer V pyramidal neurons,
but has little or no effect on layer IV neurons (McAllister et al.,
1995), whereas brain-derived neurotrophic factor (BDNF) strongly
stimulates dendrite growth in layer IV neurons with moderate effects
on layer V neurons. Distinct neurotrophin receptor expression
patterns may thus explain the unique response of each cortical layer
Development (2013) doi:10.1242/dev.087676
to different neurotrophins, highlighting that cell-intrinsic
mechanisms determine the neuronal response to particular extrinsic
cues in the environment.
In addition to controlling the specificity of dendrite patterning,
cell-intrinsic mechanisms also coordinate the timing of dendrite
morphogenesis. Neonatal RGCs rapidly lose the ability to extend
axons upon the onset of dendrite development (Goldberg et al.,
2002; Goldberg, 2004). Furthermore, RGCs from postnatal day (P)
8 animals extend significantly more dendrites than RGCs cultured
from embryonic day (E) 20 animals under identical culture
conditions, suggesting that a precisely timed cell-intrinsic program
enables neurons to rapidly develop and elaborate dendrites.
Together, these studies demonstrate the important role of cellintrinsic regulators in defining neuronal responses to extrinsic cues
and driving dendrite patterning in the nervous system.
Transcriptional control of dendritic patterning
Transcriptional regulators contribute to the specification of
neuronal dendrite arbors. In some cases, distinct dendrite
morphology can be attained by varying the levels of a single
transcriptional regulator, whereas in other cases multiple
transcriptional regulators operate synergistically to define dendrite
arbors. As we discuss below, studies in both flies and mammals
have identified a number of transcription factors that can positively
and negatively regulate distinct aspects of dendrite morphogenesis
(summarized in Table 1).
Insights from flies: individual and combinatorial actions of
transcription factors regulate dendrite patterning
Studies of the Drosophila peripheral nervous system have revealed
that transcription factors can induce dramatic changes in dendrite
patterning. For example, Jan and colleagues identified the zincfinger (ZnF)-containing transcription factor Hamlet as a key
regulator of dendrite branching (Moore et al., 2002). In loss-offunction hamlet mutants, the single, unbranched dendritic arbor of
external sensory (ES) neurons (see Glossary, Box 1) mimics the
highly branched arbor that is characteristic of multidendritic (md)
sensory neurons (see Glossary, Box 1). Expression of Hamlet in md
neuron precursors has the opposite effect, yielding dendrite
morphologies similar to those of ES neurons. Together, these
findings emphasize that a single transcription factor can drive cell
type-specific differentiation and dendrite arborization.
Forward genetic screens in Drosophila class I dendritic
arborization (da) neurons (see Glossary, Box 1) have identified more
than 70 transcription factors that may control dendrite growth
(Parrish et al., 2006). Among these, a gene encoding the BTB-ZnF
protein Abrupt is uniquely expressed in class I da neurons. Ectopic
expression of Abrupt in other classes of da neurons reduces their
complexity and size, suggesting that Abrupt limits dendrite growth
and elaboration in class I da neurons (Li et al., 2004; Sugimura et
al., 2004). By contrast, the homeodomain-containing transcription
factor Cut is expressed at different levels in class I, II, III and IV da
neurons; the four classes exhibit undetectable, low, medium and
high levels of Cut expression, respectively (Blochlinger et al., 1990;
Grueber et al., 2003). Strikingly, loss-of-function cut mutations in
neurons that normally express cut causes simplification of dendrites,
whereas overexpression of cut in class I neurons switches arbors
toward the dendrite pattern of class III neurons (Grueber et al.,
2003). Cut appears to induce actin-rich filopodia-like protrusions
that may influence branch dynamics and allow neurons to elaborate
more complex dendritic trees. Like Cut, the bHLH-PAS
transcription factor Spineless is expressed in all four classes of da
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DEVELOPMENT
REVIEW
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Development (2013) doi:10.1242/dev.087676
Table 1. Transcriptional regulators of dendrite morphogenesis
Transcriptional regulator
Organism (cell type)
Function
Key studies
Hamlet
Abrupt
Cut (Cux1)
Drosophila (ES neurons)
Drosophila (da neurons)
Drosophila (da and olfactory neurons)
Knot
Drosophila (da neurons)
Cell type-specific arborization
Limits arborization
Growth and elaboration of arbors;
dendrite targeting
Cell type-specific arborization
Spineless [aryl-hydrocarbon
(dioxin) receptor]
ACJ6 and Drifter
Foxo6 and neurogenin 2
Drosophila (da neurons)
Dendrite diversification
Moore et al., 2002
Li et al., 2004; Sugimura et al., 2004
Blochlinger et al., 1990; Grueber et al.,
2003; Komiyama and Luo, 2007
Hattori et al., 2007; Jinushi-Nakao et al.,
2007
Kim et al., 2006; Hahn, 2002
Drosophila (olfactory aPNs and lPNs)
Mammals (hippocampal, pyramidal and
cerebellar granule neurons)
Mammals (cerebellar granule neurons)
Mammals (cortical neurons)
Dendrite targeting
Control of neuronal polarization and
dendrite growth
Dendrite growth and elaboration
Dendrite growth
Mammals (hippocampal and cortical
neurons)
Mammals (cerebellar granule neurons)
Dendrite growth and elaboration
NeuroD
CREB
CREST
Sp4
MEF2A
Mammals (cerebellar granule and
hippocampal neurons)
Limits dendrite arborization and
promotes pruning
Postsynaptic dendrite differentiation
Komiyama et al., 2003
de la Torre-Ubieta et al., 2010; Hand et
al., 2005
Gaudillière et al., 2004
Redmond et al., 2002; Dijkhuizen and
Ghosh, 2005; Chen et al., 2005
Aizawa et al., 2004; Wu et al. 2007
Ramos et al., 2007; Ramos et al., 2009
Shalizi et al., 2006; Flavell et al., 2006
Known homologs are listed in parentheses following the transcription factor name.
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Together, these studies in Drosophila establish the theme that
individual transcription factors, acting either alone or in combination
with other transcription factors, may drive specific aspects of
dendrite patterning and arborization in a cell type-specific manner.
Transcriptional control of dendrite morphogenesis in the mammalian
brain
A few of the transcriptional regulators of dendrite morphogenesis in
Drosophila appear to have conserved functions in mammalian
neurons. Mammalian orthologs of Cut, termed Cut-like 1 and 2
(Cux1 and Cux2), have been characterized and may have conserved
functions in dendrite morphogenesis. In mammalian cortical
pyramidal neurons, Cux1 but not Cux2 appears to reduce dendrite
complexity by suppressing the expression of p27Kip1 (also known
as Cdkn1b) and regulating RhoA (Li et al., 2010b). Other studies
suggest that Cux1 and Cux2 operate in a cell-intrinsic manner to
stimulate the growth and branching of dendrites in upper layer
cortical neurons (Cubelos et al., 2010). In addition to Cux1 and
Cux2, other homologs of Drosophila have been identified in
mammals. However, many of these, such as the Spineless homolog
aryl-hydrocarbon (dioxin) receptor (AHR), have undefined roles in
dendrite morphogenesis in mammals (Hahn, 2002).
Several transcription factors have been implicated in dendrite
morphogenesis in the mammalian brain (Gaudillière et al., 2004;
Hand et al., 2005; Shalizi et al., 2006; Ramos et al., 2007; Shalizi et
al., 2007; de la Torre-Ubieta et al., 2010). An overarching principle of
these studies is that distinct transcription factors may be dedicated to
different phases of dendrite development. For example, de la TorreUbieta et al. identified a crucial role for the brain-enriched FOXO
transcription factor Foxo6 in the establishment of neuronal polarity
(de la Torre-Ubieta et al., 2010; Christensen et al., 2011). In both
primary cerebellar granule and hippocampal neurons, as well as in the
cerebellar cortex in vivo, knockdown of FOXO proteins leads to an
unpolarized neuronal morphology. Foxo6 directly stimulates the
expression of Pak1, which then acts locally to promote neuronal
polarization (Bokoch, 2003; Jacobs et al., 2007; Causeret et al., 2009).
At later stages of neuronal morphogenesis, Foxo6 inhibits the growth
of differentiated dendrites, thereby contributing to the characteristic
morphology of neurons with long axons and shorter dendrites. In
DEVELOPMENT
neurons. Spineless appears to enable dendrite diversification,
perhaps by endowing da neurons with the ability to respond to other
transcription factors and signaling molecules. spineless mutant flies
have more complex class I and II da neurons, whereas class III and
IV da neurons develop simpler dendritic arbors (Kim et al., 2006).
Transcription factors have also been implicated in dendritic
patterning in the Drosophila olfactory system, in which distinct cell
lineages non-redundantly target their dendrites to specific glomeruli.
For example, in addition to specifying da neuron arborization, Cut has
also been implicated in dendrite targeting in the Drosophila olfactory
system (Komiyama and Luo, 2007). The POU homeodomain
transcription factors ACJ6 and Drifter (also known as Ventral veins
lacking) also appear to define the specificity of dendrite targeting in
anterodorsal and lateral projection neurons (aPNs and lPNs,
respectively, see Glossary, Box 1). Misexpression of Drifter in aPNs,
which normally express ACJ6, or misexpression of ACJ6 in lPNs,
which normally express Drifter, causes dendrites to target the incorrect
glomeruli, suggesting that these transcription factors specify dendrite
targeting in these neurons (Komiyama et al., 2003). More recent
studies have identified a role for the BTB-ZnF transcription factor
Lola, the chromatin remodeling factor Bap55 operating through the
TIP60 complex, and the histone deacetylase Rpd3 acting via the
transcription factor Prospero in the wiring and targeting of Drosophila
olfactory projection neurons (Komiyama and Luo, 2007; Spletter et
al., 2007; Tea et al., 2010; Tea and Luo, 2011).
Transcription factors may also function in a combinatorial fashion
to specify dendrite patterning (Corty et al., 2009). The transcription
factor Knot (also known as Collier) is expressed specifically in class
IV da neurons of Drosophila, where it suppresses Cut-induced
filopodia-like protrusions (Hattori et al., 2007; Jinushi-Nakao et al.,
2007; Crozatier and Vincent, 2008). The combined expression of
Cut and Knot is essential for the correct patterning of class IV da
neurons. By contrast, Cut but not Knot is expressed in class III
neurons, which uniquely harbor actin-rich terminal branchlets
known as spiky protrusions. These terminal branchlets can be
specifically marked by Fascin (also known as Singed), which is also
required downstream of Cut for these spiky protrusions to form
correctly (Nagel et al., 2012). Thus, the pattern of expression of Cut
and Knot dictates neuronal type-specific dendrite morphology.
REVIEW
Development (2013) doi:10.1242/dev.087676
A
B
Ca2+
Ca2+
VSCCs or NMDARs
TRPC5
Cytoplasm
CaMKK
Cytoplasm
CaMKIIα
Centrosome
CaMKIγ
CaMKIIβ
P
Cdc20-APC
CaMKIV
P
Id1
NeuroD
Nucleus
P
CREB
Proteins regulating
dendrite retraction
CREST
BAF Complex
BAF53B
P
CREB
P
CBP
NeuroD
-Bdnf
-Wnt2
-Cpg15
-Other genes
Dendrite growth
and elaboration
other studies, the bHLH transcription factor neurogenin 2 (Ngn2) has
been implicated in the specification of unipolar apical dendrite
morphology in cortical pyramidal neurons (Hand et al., 2005).
Expression of wild-type Ngn2, but not the Y241F phosphorylation
mutant, induces multipolar dendrite morphology with no apical
dendrite, suggesting that Tyr241 phosphorylation is required for Ngn2
to regulate dendrites. Together, these findings establish transcriptional
mechanisms that both control the specification of dendrites and
license further steps in dendrite development.
The bHLH transcription factor NeuroD also stimulates dendrite
growth and arborization (Gaudillière et al., 2004). Knockdown of
NeuroD in primary cerebellar granule neurons and organotypic
cerebellar slices dramatically reduces dendrite growth and
arborization, but does not inhibit the growth of axons. The function
of NeuroD in dendrite growth persists into adulthood, as shown for
adult-born granule neurons of the hippocampus in NeuroD
(Neurod1) knockout mice (Gao et al., 2009). Granule neurons from
NeuroD null mice have significantly shorter dendrites than neurons
from wild-type animals. Together, these findings establish an
essential function for NeuroD in dendrite morphogenesis.
Transcriptional mediators of activity-dependent dendrite
morphogenesis
Interestingly, NeuroD activity appears to be regulated by calcium
signaling and neuronal activity (Fig. 2). The activity-regulated
protein kinase CaMKIIα stimulates NeuroD phosphorylation at
Ser336, thereby triggering NeuroD-dependent transcription and
dendrite growth (Gaudillière et al., 2004). Accordingly, disruption
of NeuroD largely abrogates the effects of CaMKIIα on dendrite
development. Thus, NeuroD acts downstream of neuronal activity
to regulate dendrite elaboration. However, the transcriptional targets
of NeuroD that mediate these effects on dendrite morphogenesis
remain to be elucidated.
Like NeuroD, the transcription factor cAMP responsive element
binding protein (CREB) mediates activity-dependent dendrite
morphogenesis in mammalian brain neurons (Fig. 2) (Dijkhuizen and
Ghosh, 2005). In addition to the protein kinase CaMKIV, the small
GTP-binding protein Rap1 appears to contribute to calcium-dependent
activation of CREB signaling, suggesting that multiple pathways
might link calcium influx with CREB-dependent transcription and
dendrite growth (Chen et al., 2005). Expression of dominant-negative
CREB suppresses voltage-gated calcium channel- and CaMKIVinduced dendrite growth (Redmond et al., 2002), suggesting that
CREB-dependent transcription is required for activity-dependent
dendrite growth and that CREB acts as a node in activity-dependent
signaling. Although the specific targets of CREB that control dendrite
growth remain to be fully characterized, BDNF has been identified as
one target that promotes dendrite growth in both cortical and
cerebellar neurons (McAllister et al., 1995; McAllister et al., 1996;
Schwartz et al., 1997; Horch et al., 1999; Mertz et al., 2000).
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DEVELOPMENT
Fig. 2. Calcium-mediated regulation of dendrite morphogenesis. Calcium-regulated control occurs throughout dendrite morphogenesis – during growth
and elaboration as well as during dendrite pruning and retraction. (A) Neuronal depolarization with subsequent calcium entry via voltage-sensitive calcium
channels (VSCCs) or NMDA receptors (NMDARs) triggers the activation of calcium/calmodulin-dependent kinase (CaMK) family members, thereby directing
transcription factor activity in the nucleus. CREB functions downstream of CaMKIγ or CaMKIV, while the transcription factor NeuroD is phosphorylated and
activated by CaMKIIα. Other transcriptional regulators such as CBP bind to CREB and influence transcription. At the level of chromatin, the chromatin
remodeling complex nBAF plays a role in regulating activity-dependent dendrite growth. CREST binds to the nBAF complex and, in turn, controls gene
expression. Together, these diverse mechanisms provide complex, yet tightly regulated, control of gene expression relevant for dendrite growth, including Bdnf,
Wnt2 and Cpg15 (Nrn1). (B) During later stages of dendrite development, calcium regulates ubiquitin signaling at the centrosome to drive dendrite retraction
and pruning. Calcium influx via the membrane channel TRPC5 activates CaMKIIβ, which phosphorylates and inhibits the major ubiquitin ligase Cdc20-APC at
the centrosome. As a result, the Cdc20-APC substrate Id1 accumulates at the centrosome leading to dendrite retraction and pruning.
REVIEW
Role of other transcriptional regulators
In granule neurons of the cerebellar cortex, the transcriptional
regulator SnoN (also known as Skil) controls neuronal branching,
including dendrite branching, in an isoform-specific manner (Huynh
et al., 2011). In Drosophila, polycomb proteins, which are broadly
involved in transcriptional silencing, have been implicated in the
maintenance of Drosophila sensory neuron dendrites (Parrish et al.,
2007a).
Transcription factors may also repress dendrite branching. The
ZnF transcription factor Sp4, for example, has been implicated in
the patterning of granule neuron dendrites (Ramos et al., 2007).
Knockdown of Sp4 in primary granule neurons and in organotypic
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cerebellar slices leads to the exuberant branching of dendrites
(Ramos et al., 2007). In addition, activity-induced dendritic
remodeling is blocked by Sp4 knockdown, suggesting that Sp4
might restrict branch formation and promote activity-dependent
pruning. Follow-up studies revealed that Sp4 binds to the promoter
of neurotrophin 3 (NT-3, or Ntf3) and represses its activity, thereby
reducing NT-3 expression and limiting dendrite branching in
neurons (Ramos et al., 2009). Thus, distinct transcription factors
may positively or negatively regulate dendrite arborization in the
mammalian brain, offering a highly specific but complex layer of
control over dendrite morphogenesis.
The role of steroid hormones
Like transcription factors, steroid hormones operate in the nucleus
to regulate dendrite development. The γ neurons of the Drosophila
mushroom body (see Glossary, Box 1), for example, appear to be
differentially regulated by the nuclear receptor Ftz-f1 and its
homolog Hr39 (Boulanger et al., 2011). Although these analyses
primarily focused on axonal pruning and remodeling, the authors
suggest a role for Ftz-f1 in triggering expression of the steroid
hormone receptor Ecr-B1 and downregulating expression of Hr39,
thereby inducing pruning of γ neuron dendrites. By contrast, Hr39
competes with endogenous Ftz-f1 and thereby decreases Ecr-B1
levels to disrupt pruning. Thus, Ftz-f1 and Hr39 exert opposing
effects on dendrite arbors by acting as a rheostat for Ecr-B1
expression. Furthermore, recent studies of Drosophila da neurons
suggest that, in the presence of the steroid hormone ecdysone,
Ecr-B1 binds to CREB-binding protein (CBP) and, in collusion
with the epigenetic factor Brm, induces the acetylation of H3K27
at the Sox14 gene locus (Kirilly et al., 2011). Thus, steroid
hormones may operate through epigenetic mechanisms to regulate
dendrite morphogenesis, although the biochemical links remain
unknown.
Cytoskeleton-mediated control of dendritic morphogenesis
Cytoskeletal regulators act on structural proteins within the soma
and dendrites to control dendrite morphogenesis throughout
development. Early in development, these regulators drive
fundamental changes in dendrite growth and arborization, whereas
at later stages they provide mechanisms for the finely tuned control
of the dendrite arbor. By restructuring the actin and microtubule
skeleton, these regulators can mediate direct changes in dendrite
arborization and length.
Rho family GTPases and actin cytoskeletal regulators
The Rho family of GTPases modulates the cytoskeleton to regulate
dendrite growth and branching in invertebrate and mammalian
neurons (Leemhuis et al., 2004; Newey et al., 2005; Chen and
Firestein, 2007). These proteins cycle between an activated GTPbound state and an inactive GDP-bound state. The small GTPase
RhoA limits dendrite growth, whereas Ras-related C4 botulinum
toxin substrate 1 (Rac1) and Cdc42 appear to drive dendrite
elaboration (Scott and Luo, 2001). Constitutively active RhoA
expression in Drosophila central nervous system neurons, Xenopus
RGC and central neurons, chick RGC explants, and rat hippocampal
slices reduces dendrite length and the volume of the dendritic field
(Ruchhoeft et al., 1999; Lee et al., 2000; Li et al., 2000; Nakayama
et al., 2000; Wong et al., 2000). RhoA loss-of-function mutations in
flies cause mushroom body neurons to overshoot their boundaries,
leading to abnormal dendritic fields (Lee et al., 2000). In contrast to
RhoA mutants, loss of Rac1 in flies reduces dendrite complexity and
size in mushroom body neurons (Ng et al., 2002). Similarly, in larval
DEVELOPMENT
The SYT-related nuclear protein calcium-responsive transactivator
(CREST, also known as Ss18l1) also mediates calcium-induced
dendrite growth (Fig. 2). Using a transactivator trap approach,
Ghosh and colleagues identified CREST as a key downstream
effector of calcium influx (Aizawa et al., 2004). Crest knockout
mice have impaired dendrite growth in the cortex and hippocampus,
and cortical neurons cultured from these mice fail to elaborate
dendrites in response to neuronal activity. CREST operates as a
transcriptional regulator, and studies from Crabtree and colleagues
revealed that CREST binds to subunits of the neuron-specific
chromatin remodeling Brg/Brm-associated factor complex (nBAF)
to drive activity-dependent dendrite growth (Wu et al., 2007).
CREST and nBAF interact in neurons, where, in combination with
the key subunit nBAF53b (also known as Actl6b), they control the
expression of genes involved in neuronal morphogenesis. Using
Baf53b knockout mice, Gap43, Stmn2, Rap1a, Gprin1 and Ephexin1
(also known as Ngef) were identified as targets of this complex.
Expression of Ephexin1 corrected dendrite defects in Baf53b
knockout neurons and reversed their impairment in activitydependent dendrite growth (Wu et al., 2007), consistent with a role
of Ephexin1 in balancing Rho and Rac/Cdc42 signaling (Shamah et
al., 2001; Sahin et al., 2005). Several homologs of nBAF have been
identified in Drosophila as important regulators of dendrite
development (Parrish et al., 2006), suggesting that this signaling
pathway might be conserved.
As dendrites are pruned, they begin to form postsynaptic
structures specialized for contact with axons. In the cerebellum, for
example, granule neurons form cup-like structures called dendritic
claws (Hámori and Somogyi, 1983). One transcription factor
implicated in dendrite differentiation is myocyte enhancer factor 2A
(MEF2A). Knockdown analyses reveal that MEF2A is required for
the morphogenesis of dendritic claws in the cerebellar cortex in vivo
(Shalizi et al., 2006). Neuronal activity stimulates calcineurin, which
induces the dephosphorylation of MEF2A at Ser408 and promotes
a sumoylation-to-acetylation switch at Lys403, thereby activating
MEF2A and inhibiting dendritic claw differentiation. The SUMO E3
ligase PIASx (also known as Pias2) induces MEF2 sumoylation and
consequently stimulates dendritic claw differentiation in the
cerebellar cortex in vivo (Shalizi et al., 2007). Biochemical and
nuclear magnetic resonance (NMR) structural studies suggest that
Ser408 phosphorylation stimulates the ability of the SUMO E2
enzyme Ubc9 (also known as Ube2i) to trigger SUMO conjugation
at Lys403 (Mohideen et al., 2009). These findings establish a
calcium-regulated MEF2 sumoylation switch that transcriptionally
controls dendrite differentiation. Although several transcription
factors have emerged as key regulators of dendrite patterning in
invertebrates and mammals, it will be essential to understand how
these distinct pathways are ultimately integrated to sculpt the mature
dendrite arbor.
Development (2013) doi:10.1242/dev.087676
class IV da neurons, Rac1 and the actin-stabilizing protein
tropomyosin regulate dendrite growth and branching (Lee et al.,
2003; Li and Gao, 2003). Loss of Cdc42 in vertical system neurons
(see Glossary, Box 1) of the Drosophila visual system interferes
with typical branching patterns and tapering of dendrites (Scott et
al., 2003), whereas hyperactivation of Cdc42 in mice bearing
mutations in the Cdc42 GAP NOMA-GAP (also known as
Arhgap33) leads to simplified cortical dendrites in vivo by regulating
the actin regulator cofilin (Rosário et al., 2012). In other systems,
including Xenopus optic tectal neurons (see Glossary, Box 1) and
mammalian RGCs, Rac1 and to a lesser extent Cdc42 selectively
increase dendrite branch extension and retraction (Li et al., 2000;
Wong et al., 2000).
How might Rho and Rac activity be regulated? Interestingly,
neuronal depolarization induced by NMDA and glutamate
receptors in the retina appears to regulate dendrite dynamics
through Rho and Rac (Wong et al., 2000). Studies in hippocampal
neurons have identified the GEF Tiam1 as a crucial molecular link
between NMDA signaling and Rac1 (Tolias et al., 2005).
Similarly, the GEF family of Ephexins regulates the activity of
RhoA, Rac and Cdc42 (Shamah et al., 2001; Sahin et al., 2005;
Margolis et al., 2010). Interestingly, different Ephexin proteins
operate downstream of distinct Eph receptors and have divergent
effects on Rho and Rac activation (Shamah et al., 2001; Margolis
et al., 2010). For example, Ephexin5 (also known as Arhgef15)
specifically stimulates RhoA activity with little or no effect on Rac
and Cdc42 (Margolis et al., 2010). Although Ephexins regulate
axon growth cone dynamics and synaptic development (Shamah et
al., 2001; Sahin et al., 2005; Margolis et al., 2010), a function for
Ephexins, specifically Ephexin1, in dendrite morphogenesis has
been described (Wu et al., 2007). Beyond GEF-dependent
activation, Rac activity has also been linked to non-canonical Wnt
signaling via catenins in hippocampal neurons (Yu and Malenka,
2003; Rosso et al., 2005; Peng et al., 2009). This pathway is
regulated by the postsynaptic protein Shank and the origin
recognition core complex, both of which have functions in
dendrite morphogenesis (Huang et al., 2005; Quitsch et al., 2005).
Together, these findings suggest that Rho family GTPases might
be essential in transducing extracellular cues and other signals to
direct structural changes within neurons.
Several studies have aimed to identify the key downstream
effectors of Rho family GTPases. RhoA activates the Rho-associated
kinase (ROK), and in hippocampal neurons ROK inhibition
suppresses the reduction in dendrite length induced by constitutively
active RhoA expression (Nakayama et al., 2000), suggesting that
ROK is required for RhoA function in dendrite morphogenesis.
ROK, in turn, controls the phosphorylation of myosin light chains
and actomyosin contractility (Kimura et al., 1996; Hirose et al.,
1998; Winter et al., 2001). Compared with RhoA, less is known
about the downstream effectors of Rac1 and Cdc42 in the control of
dendrite morphogenesis. Rac1 and Cdc42 might converge on a
common signaling pathway. Consistent with this model, the
serine/threonine kinase Pak1 appears to be activated by Rac1 and
Cdc42 and induces dendrite elaboration in immature cortical
neurons (Hayashi et al., 2007). Rac1 and Cdc42 may also activate
the Arp2/3 complex (Chhabra and Higgs, 2007). However, further
research is required to elucidate additional upstream regulators and
downstream effectors of Rho family GTPases.
Like Rho GTPases, the actin polymerization factor Enabled (Ena)
appears to regulate the actin cytoskeleton to drive dendrite
patterning. In Drosophila md sensory neurons, loss-of-function
mutations in ena cause dendrites to turn dorsally, and these dendrites
Development (2013) doi:10.1242/dev.087676
fail to reach segment boundaries (Gao et al., 1999). Interestingly,
Ena and the tyrosine kinase Ableson (Abl) appear to act downstream
of the guidance receptor Roundabout (Robo) and the receptor
tyrosine phosphatase Dlar (also known as Lar) (Wills et al., 1999;
Bashaw et al., 2000). Although Ena and its homologs form a
complex with actin cytoskeletal proteins and regulate actin dynamics
(Lanier and Gertler, 2000), the specific molecular effectors of Ena
in dendrite morphogenesis remain to be elucidated.
Motor proteins and microtubule regulators
Following extension of the actin cytoskeleton, dendrites must be
stabilized by microtubules to maintain adequate structural integrity,
a process that involves a number of microtubule motor and transport
proteins. In contrast to those in axons, microtubules within dendrites
support transport in both directions (Baas et al., 1988; Baas et al.,
1989). As demonstrated by depletion of the motor protein CHO1
(also known as MKLP1 or KIF23) in sympathetic neurons, these
bidirectional microtubules are essential for the formation and
maintenance of dendrites (Sharp et al., 1997; Yu et al., 2000). In
addition to CHO1, many other microtubule transport proteins
contribute to dendrite development. For example, in Drosophila,
loss-of-function mutations in the genes encoding the minus-enddirected dynein motor protein Dhc64 and its associated protein
Lissencephaly1 (Lis1) inhibit dendrite growth, branching, and
maturation in mushroom body neurons (Liu et al., 2000; Smith et
al., 2000). Interestingly, LIS1 (also known as PAFAH1B1) mutations
in humans result in the loss of gyri and sulci, which leads to a
smooth appearance of the cortex known as lissencephaly. Although
this pathology is primarily due to defects in the migration of cortical
neurons, heterotropic pyramidal neurons of the hippocampus and
early cortical neurons in heterozygous Lis1 (Pafah1b1) mutant mice
exhibit reduced dendrite length and branching (Fleck et al., 2000;
Cahana et al., 2001). Additional motor proteins, including the
kinesin family member Kif5, have been implicated in the trafficking
of proteins required for dendrite growth (Hoogenraad et al., 2005).
Other regulators appear to control the activity of motor proteins:
Nna1 (also known as Agtpbp1), for example, regulates microtubule
stability through intranuclear lysyl oxidase propeptide and NF-κB
RelA signaling to direct Purkinje cell dendrite development (Li et
al., 2010a). Collectively, these studies establish the important role
of microtubule motor proteins in the formation and maintenance of
dendrites.
Several molecules that link microtubule dynamics to the actin
cytoskeleton are also emerging as important regulators of dendrite
growth, supporting the idea that changes in the actin cytoskeleton
of dendrites must subsequently be stabilized by microtubules. For
instance, in the case of Lis1 and dynein, these proteins form a
complex with Nudel, which is a p35/Cdk5 substrate (p35 is a
neuronal-specific activator of Cdk5) (Niethammer et al., 2000;
Sasaki et al., 2000). Interestingly, p35/Cdk5 activity can be
regulated by Rac (Nikolic et al., 1998), suggesting that p35/Cdk5
might act as signaling link between the actin cytoskeleton and
microtubules in neurons. In Drosophila, the large cytoskeletal
linker protein Kakapo (Kak, also known as Short stop), which has
the vertebrate homolog MACF, contains domains that bind to actin
and microtubules (Gregory and Brown, 1998; Strumpf and Volk,
1998). In kak mutant flies, microtubule structure is disrupted in
numerous cell types, and, accordingly, dendrites in md neurons
and motoneurons exhibit defective branching (Prokop et al., 1998;
Gao et al., 1999). Together, these studies suggest that linking actin
and microtubule dynamics is crucial for the growth and branching
of dendrites.
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DEVELOPMENT
REVIEW
REVIEW
The growth and elaboration of dendrites requires large amounts of
plasma membrane and protein, demanding dedicated mechanisms
for polarized trafficking of cargo into new branches (Corty et al.,
2009). Compartmentalized Golgi, known as Golgi outposts, are
important components of the secretory pathway that are found in
invertebrate and mammalian dendrites (Horton and Ehlers, 2003;
Horton et al., 2005; Ye et al., 2007). In rat hippocampal neurons,
Golgi outposts tend to be found in longer, highly branched dendrites,
and perturbations of Golgi trafficking in these neurons disrupts
dendrite growth and maintenance (Horton et al., 2005; Pfenninger,
2009). Moreover, local ablation of Golgi outposts reduces the branch
dynamics of Drosophila da neurons (Ye et al., 2007). How might
Golgi outposts control dendrite morphogenesis? A recent study
suggests that Golgi outposts directly nucleate microtubules via the
proteins γ-tubulin and CP309, a Drosophila homolog of the
mammalian centrosomal matrix protein AKAP450 (also known as
Akap9) (Ori-McKenney et al., 2012). There are likely to be
additional mechanisms and functions downstream of Golgi outposts
that remain to be defined.
Recent studies suggest that the dendritic endoplasmic reticulum
(ER) might also play a role in the localization of essential proteins
at branch points, highlighting an important role for protein kinase C
(PKC) and the ER protein CLIMP-63 (also known as Ckap4) in
spatially limiting AMPA receptors in response to type I metabotropic
glutamate receptor (mGluR) signaling (Cui-Wang et al., 2012).
Remarkably, local zones of ER complexity reside at branch points
that work with these proteins to concentrate AMPA receptors. Thus,
active mechanisms for localizing the secretory machinery, including
the Golgi and ER, at sites of dendrite growth and remodeling may
regulate dendrite development.
In forward genetic screens in flies, several proteins that mediate
ER to Golgi transport, such as Dar2, Dar3 and Dar6, which are
orthologs of the yeast proteins Sec23, Sar1 and Rab1, respectively,
are required for dendrite elaboration in class IV da neurons (Ye et
al., 2007). For example, Dar3 is necessary for vesicle formation as
proteins traffic from the ER to the Golgi. Correspondingly, Dar3
mutants have diffuse Golgi outposts and disrupted dendrite growth.
Knockdown of the Dar3 homolog Sar1 in rat hippocampal neurons
has similar effects and specifically disrupts dendrite but not axon
development (Ye et al., 2007), suggesting that flies and mammals
use evolutionarily conserved mechanisms to control dendritic
secretory trafficking.
How might Golgi proteins localize at sites of active dendrite
remodeling? In Drosophila, the golgin coiled-coil adaptor protein
Lava lamp (Lva) controls Golgi outpost distribution by associating
with the microtubule-based motor complex dynein-dynactin.
Consistent with this function, dominant-negative Lva causes Golgi
outposts to shift to proximal dendrites, leading to a distal to
proximal shift of dendrite branching in da neurons (Ye et al., 2007).
Follow-up studies have found that additional mutations in dynein
light intermediate chain 2 and dynein intermediate chain phenocopy
the effect of lva mutations on Golgi outposts and dendrite
morphogenesis (Satoh et al., 2008; Zheng et al., 2008). Because the
dynein complex is a minus-end-directed motor, these findings raise
the intriguing possibility that dynein functions to traffic key
components of the branching machinery to expanding dendrite
arbors.
Key regulators of dendrite morphogenesis may act locally at the
Golgi apparatus to control dendrite morphogenesis. Litterman et al.
4664
have uncovered the E3 ubiquitin ligase Cul7-Fbxw8 as a crucial
regulator of both Golgi morphogenesis and dendrite development
(Litterman et al., 2011). Cul7-Fbxw8 localizes at the Golgi
apparatus in neurons, and inhibition of Cul7-Fbxw8 impairs Golgi
morphogenesis and function in granule neurons and consequent
dendrite arbor elaboration in the rodent cerebellar cortex in vivo
(Litterman et al., 2011). The cytoskeletal regulator Obsl1 interacts
with Cul7-Fbxw8 and localizes Cul7 to the Golgi apparatus in
neurons, and thus promotes dendrite growth (Litterman et al., 2011).
Remarkably, mutations of CUL7 and OBSL1 cause the human
developmental disorder 3M syndrome (Huber et al., 2005;
Maksimova et al., 2007; Hanson et al., 2009), raising the question
of whether dendrite abnormalities might occur in this disorder.
Taken together, these findings suggest that protein complexes might
act locally at the Golgi apparatus to direct dendrite morphogenesis.
Along with the secretory pathway, the endocytic pathway may
regulate dendrite growth and branching by influencing the density
of cell surface receptors involved in dendrite morphogenesis (Jan
and Jan, 2010). For example, components of the early endocytic
pathway, such as the small GTPase Rab5, facilitate arborization of
Drosophila da neurons in a dynein-dependent manner (Satoh et al.,
2008). By contrast, mutations in the coiled-coil protein Shrub, the
Drosophila homolog of yeast Snf7, which mediates endosome to
lysosome trafficking via the ESCRT-III complex, cause exuberant
branching of dendrites in da neurons (Sweeney et al., 2006).
Interestingly, in yeast, Snf7 is essential for the formation of
multivesicular bodies (Teis et al., 2008; Saksena et al., 2009), raising
the question of whether these endosomal compartments have a role
in dendrite patterning. What are the specific cell surface molecules
that regulate dendrite morphogenesis? Recent data implicate the
clathrin adaptor-associated kinase Nak in higher order dendrite
growth (Yang et al., 2011). Nak appears to interact with aspects of
the endocytic pathway to direct the dendritic localization of clathrin
puncta at branch points and dendritic tips, where it facilitates the
internalization of the Drosophila L1CAM homolog Neuroglian. In
the future, in addition to clarifying the endocytic machinery relevant
to dendrite morphogenesis, it will be essential to identify additional
cargo of this pathway that directs dendrite development.
Factors that regulate dendritic field size and scaling
In order for information to be transmitted with high fidelity, dendrite
arbors must appropriately cover their target receptive fields of
innervation. Dendrites must also grow to an appropriate size to
avoid the overlap of processes from similar neuron types. As we
discuss below, Hippo family members and PI3K-mTor signaling
proteins have emerged as important drivers of dendritic field size
and the scaling of dendritic arbors.
Hippo family members
The Ste20 family kinase Hippo regulates organ size in mammals and
flies (Pan, 2007). In Drosophila, Hippo is positively regulated by
Salvador (Sav) and phosphorylates and activates Warts (Wts), a
nuclear DBF2-related (NDR) kinase. In Drosophila da neurons, this
complex inhibits components of the polycomb repressor complex
(PRC) to block transcriptional silencing (Parrish et al., 2007a).
Consistent with this model, mutations in Hippo pathway members
or Polycomb group (PcG) genes impair dendrite maintenance in
class IV da neurons, leading to gaps in dendritic fields (Emoto et al.,
2006; Parrish et al., 2007a), establishing a crucial role for Hipporegulated Sav-Wts signaling in dendrite maintenance.
Hippo is also a key regulator of the NDR kinase Tricornered
(Trc), which is activated by Furry (Fry). In Drosophila class IV da
DEVELOPMENT
Trafficking and membrane remodeling during dendrite
morphogenesis: a role for Golgi and endoplasmic reticulum
proteins
Development (2013) doi:10.1242/dev.087676
neurons, mutations in trc or fry were initially believed to render
dendrites insensitive to contact-mediated suppression of outgrowth,
leading to overlapping dendritic fields and loss of dendritic tiling
(Emoto et al., 2006). However, new analyses from Han et al.
demonstrate that trc and fry mutants fail to confine dendrites in a
two-dimensional plane, allowing expansion of dendrites in three
dimensions (Han et al., 2012). Consequently, dendrites in these
mutants are able to avoid contact-mediated repulsion, resulting in
overlapping receptive fields and the loss of tiling. Interestingly,
components of TOR complex 2 (TORC2), including Sin1,
Rapamycin-insensitive companion of Tor (Rictor) and Tor, form a
complex with Trc and trigger its activation and phosphorylation.
Accordingly, mutations in these genes disrupt the tiling of class IV
da neurons by failing to restrict dendrites to a two-dimensional plane
(Koike-Kumagai et al., 2009; Han et al., 2012). Importantly, these
mechanisms appear to be evolutionary conserved: SAX-1 and SAX2, the Caenorhabditis elegans homologs of Trc and Fry,
respectively, also drive dendritic tiling. Together, these studies
suggest that Hippo signaling regulates Trc-Fry and Wts-Sav
signaling to coordinate dendrite tiling and maintenance (Jan and Jan,
2010).
In the mammalian brain, NDR kinases 1 and 2 (also known as
Stk38 and Stk38l) regulate dendrite arborization and dendritic spine
development (Ultanir et al., 2012). Knockdown of NDR1/2 or
expression of dominant-negative NDR mutants increases dendrite
arborization and proximal branching in pyramidal neurons. AP2
associated kinase (AAK1) and the GEF Rabin8 have been identified
as substrates of NDR1/2 (Ultanir et al., 2012). Accordingly, these
intracellular vesicular trafficking proteins drive dendrite growth and
spine development, respectively.
PI3K-mTOR signaling proteins
Several studies in both flies and mammals have suggested a function
for phosphoinositide 3-kinase (PI3K) signaling in dendrite scaling
and development. In flies, the PI3K-mammalian target of rapamycin
(mTOR) pathway restricts dendrite development (Parrish et al.,
2009); however, this pathway is regulated extrinsically by
expression of the microRNA bantam by neighboring epithelial cells,
which in turn dampens Akt activity in the da neurons. In mammalian
neurons, the PI3K-Akt-mTOR pathway promotes dendrite growth
(Jaworski et al., 2005; Kumar et al., 2005). Additional studies using
neurons cultured from Reeler mice and wild-type littermates reveal
that reelin stimulates mTOR-S6 kinase 1 signaling in a Dab1dependent manner (Jossin and Goffinet, 2007). Strikingly,
pharmacologic inhibition of PI3K, Akt or mTOR in hippocampal
neurons blocks the stimulatory effects of reelin on dendrite growth
(Jossin and Goffinet, 2007). Together, these findings suggest that
reelin operates upstream of PI3K and target of rapamycin complex
1 and 2 (TORC1/2) signaling to regulate dendrite morphogenesis.
Interestingly, mutations in components of target of TORC2,
including Sin1, Rictor and Tor, have also been implicated in dendrite
patterning in Drosophila. These TORC2 components form a
physical complex with Trc to drive class IV da neuron dendritic
tiling (Koike-Kumagai et al., 2009). Collectively, these studies
suggest that Ras-PI3K-mTOR as well as TORC2 signaling regulate
dendrite development, with potential roles in dendrite scaling and
tiling.
Cell cycle-regulated ubiquitin ligases and dendrite
development
A growing body of literature has identified novel functions for cell
cycle proteins in postmitotic neurons (Kim and Bonni, 2007; Yang
Development (2013) doi:10.1242/dev.087676
et al., 2010; Puram and Bonni, 2011). Nearly a decade ago, the
major ubiquitin ligase Cdh1-APC was shown to restrict axon
growth in postmitotic neurons (Konishi et al., 2004), a finding that
triggered numerous analyses of the regulation and substrates of
this protein complex (Huynh et al., 2009; Lasorella et al., 2006;
Stegmuller et al., 2006). In light of Cdh1-APC function in axons,
the role of the related ubiquitin ligase Cdc20-APC has been also
characterized in neurons (Kim et al., 2009; Puram et al., 2010).
These studies revealed that components of the Cdc20-APC
complex are expressed in the developing brain, where it promotes
dendrite growth and elaboration (Kim et al., 2009). The
centrosome-associated histone deacetylase 6 (Hdac6) promotes the
polyubiquitylation of Cdc20, thereby stimulating the ubiquitin
ligase activity of Cdc20-APC. In turn, centrosomal Cdc20-APC
triggers the polyubiquitylation and degradation of the HLH protein
inhibitor of DNA binding 1 (Id1) to stimulate dendrite
development. Centrosomal Id1 controls dendrite development by
interacting with the ubiquitin receptor Rpn10 (also known as S5a
or Psmd4) and thereby inhibiting proteasome activity at the
centrosome in neurons (Puram et al., 2013). The Cdc20-APC cellintrinsic pathway of dendrite morphogenesis appears to be
regulated upstream through cell-extrinsic cues such as calcium
signaling via the canonical calcium channel TRPC5 and the major
protein kinase CaMKIIβ (Fig. 2) (Puram et al., 2011a; Puram et
al., 2011b). In the future, it will be essential to determine whether
additional regulators of centrosomal signaling can mediate the
integration of cell-extrinsic cues and cell-intrinsic signaling driven
by cell cycle proteins.
RNA targeting and local protein translation in dendrites
In order to rapidly extend and maintain dendrite branches, neurons
must rapidly synthesize proteins locally within dendrites. Local
translation appears to have a central role in dendrite morphogenesis
(Chihara et al., 2007). The RNA-binding proteins Pumilio and
Nanos, which were originally identified as mRNA targeting proteins
in Drosophila embryos, are required for dendrite patterning in class
III and IV da neurons but not in class I and II neurons (Ye et al.,
2004). In addition, following the period of initial dendrite growth,
the maintenance and further branching of class IV da neurons in
larva depends on dendritic targeting of nanos mRNA along with
Glorund and Smaug, which regulate nanos translation by
recognizing stem loops in its 3′ untranslated region (UTR)
(Brechbiel and Gavis, 2008). Similarly, staufen 1 (Stau1), a doublestranded RNA-binding protein, has been linked to dendritic RNA
localization in neurons, translational control and mRNA decay.
Cultured hippocampal neurons from mutant mice with truncated
Stau1 show defective dendritic targeting of Stau1 and β-actin (Actb)
mRNA-containing ribonucleoproteins, and simplified dendritic
arbors (Vessey et al., 2008). However, these animals have no
obvious behavioral deficits, suggesting that Stau1 is likely to act
redundantly with other local translation mechanisms. What might
label specific mRNAs for dendritic targeting? Buckley et al. have
identified ID element retrotransposons, a retained class of short
interspersed repetitive elements (SINEs), within the introns of
several dendritically targeted mRNAs (Buckley et al., 2011). These
sequences are sufficient for targeting both endogenous and
exogenous transcripts to dendrites, and, accordingly, appear to
influence protein distribution within the cell. Thus, sequencespecific elements as well as RNA-protein interactions may direct
local dendritic translation.
In Xenopus, the mRNA-binding protein cytoplasmic
polyadenylation element binding protein 1 (CPEB1) regulates
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DEVELOPMENT
REVIEW
REVIEW
Development (2013) doi:10.1242/dev.087676
activity-dependent dendrite morphogenesis in the visual system.
Using morpholino-mediated knockdown and mutant expression
studies, Bestman and Cline proposed a role for CPEB1 in the local
translation of mRNAs (Bestman and Cline, 2008). Consistent with
these findings, CaMKII phosphorylates CPEB in hippocampal
neurons, which induces the interaction of CPEB with cytoplasmic
polyadenylation element (CPE)-like sequences in mRNA, thus
stimulating translation (Atkins et al., 2004). A targeting function for
CPEB has been proposed. Upon depolarization, CPEB is recruited
to CPE-like sequences in the 3′ UTR of BDNF mRNA, targeting the
mRNA to hippocampal neuron dendrites (Oe and Yoneda, 2010).
Like CPEB1, Fragile X mental retardation protein (FMRP) regulates
the trafficking and translation of mRNAs to the neuronal periphery,
and thereby influences dendrite morphogenesis (Bagni and
Transcriptional regulators
and steroid hormones
TF
Target
gene
Other genes
regulating
dendrites
Cytoskeletal regulators
GTP
Rac1
Greenough, 2005). However, the precise mechanism by which
FMRP controls dendrite patterning remains unclear. These studies
suggest that mRNA-binding proteins such as CPEB1 and FMRP are
crucial regulators of mRNA targeting and translation in dendrites.
Accordingly, defects in these cellular mechanisms may have
dramatic consequences for the proper generation of neuronal
circuitry and brain function.
Conclusions and perspectives
Recent studies reveal an enormous degree of complexity in the
signaling mechanisms that control dendrite growth, patterning and
maintenance. Although numerous cell-intrinsic regulators, ranging
from transcription factors to cytoskeletal proteins, orchestrate
dendrite morphogenesis (summarized in Fig. 3), there are several
Growth and
branching
Pruning
Hamlet (md)
Cut, Knot and Fascin
Spineless (da)
NeuroD
CREB
CREST
Hamlet (ES)
Abrupt
Spineless (da)
Sp4
Ftzf1-EcrB1
Rac1
Cdc42
Tiam1
Pak1
Arp2/3
RhoA
Ephexin5
ROK
CHO1
Kif5
Nna1
Kak
Dhc64/Lis1
Nudel
Golgi outposts
Dendritic ER – CLIMP63, PKC
Dar2, Dar3, Dar6
Sar1
Lava lamp
Cul7-Fbxw8
Rab5
Nak
Shrub
Hippo-Sav-Wts
NDR1/2-AAK1 and Rab8
mTor-S6 kinase 1-Dab1
miRNA bantum-PI3K-mTOR
Differentiation
and patterning
Differentiation:
MEF2A
Targeting:
ACJ6 and Drifter
Lola
Bap55-TIP60
Rpd3-Prospero
Targeting:
Enabled
Abl
Cell-intrinsic regulators
Motor proteins
Dhc64
Lis1
Secretory and endocytic pathways
Hippo pathway and PI3K signaling
P
Sav
Hippo
Wts
PRC
TF
Target
gene
Tiling:
Hippo-Trc-Fry
TORC2
Ub
Ub
Ub
HDAC6
Cdc20
Id1
HDAC6-Cdc20-APC-Id1-S5a
TRPC5-CaMKIIβ-Cdc20-APC
Cul7-Fbxw8
Centrosome
Fig. 3. A summary of the key cell-intrinsic regulators of distinct stages of dendrite morphogenesis. Individual proteins or their signaling cassettes
involved at each stage of dendrite morphogenesis are indicated, as described in the main text. In cases in which a given factor has opposing effects on two
different populations of neurons, the neuron type is listed in parentheses.
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DEVELOPMENT
Ubiquitin ligase pathways
REVIEW
have a major impact on our understanding of dendrite
morphogenesis in the years to come. For example, a recent study has
identified a role for the microRNA bantam in repressing Akt activity
and blocking the regeneration of dendrites in Drosophila da neurons
(Ultanir et al., 2012). Similarly, the role of organelles such as the
primary cilium in dendrite morphogenesis remains to be elucidated.
Defects in dendrite morphogenesis have been observed in neurons
with conditional deletion of cilia (Song et al., 2012), but the
underlying signaling mechanisms remain poorly characterized. The
authors suggest that Wnt signaling might be dysregulated, thereby
mediating aberrations in dendrite patterning. There has also been an
explosion of interest in the secretory pathway and its functions in
diverse aspects of biology, and the role of the secretory pathway
machinery in dendrite morphogenesis is no exception (Kumamoto
et al., 2012).
Characterizing the pathways regulating dendrite morphogenesis
is likely to have profound consequences for our understanding of
developmental disorders of cognition. Abnormalities in dendrite
morphogenesis have been described in diverse neurological
disorders including autism spectrum disorders (ASD), Down
syndrome and Fragile X (Al-Bassam et al., 2012), as well as
neurodegenerative disease (Takashima et al., 1981; Becker et al.,
1986; Armstrong, 1995; Irwin et al., 2000; Kaufmann and Moser,
2000; Dierssen and Ramakers, 2006; Pardo and Eberhart, 2007).
Psychiatric disorders such as schizophrenia may also be
characterized by dendritic abnormalities (Graveland et al., 1985;
Selkoe et al., 1987). In all these disorders, it remains unclear
whether dendrite defects represent the cause or effect of the disease;
however, it is tempting to speculate that reversing dendrite
abnormalities in these disorders might prove at least partially
clinically beneficial. Although dendrite development is likely to
require a delicate balance between numerous molecular pathways,
improving our understanding of these diverse regulators might
render the manipulation of dendrite patterning a real possibility in
the future.
Acknowledgements
We thank Luis Mejia, Luis de la Torre and other members of the A.B. laboratory for
helpful discussions and critical reading of the manuscript.
Competing interests
The authors declare no competing financial interests.
Funding
Work in the authors’ laboratories is supported by a grant from the National
Institutes of Health (NIH) to A.B. and from the NIH Medical Scientist Training
Program to S.V.P. Deposited in PMC for release after 12 months.
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