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REVIEW 1455
Development 134, 1455-1463 (2007) doi:10.1242/dev.000117
Foxe view of lens development and disease
Olga Medina-Martinez and Milan Jamrich*
Introduction
The classical studies of lens development (Lewis, 1904; Spemann,
1901) led to several important insights into the processes of
induction and tissue specification. Since lens development has many
features in common with the development of other placodal
structures, such as the anterior pituitary, otic vesicle, olfactory
epithelium, trigeminal and epibranchial placodes, studies of lens
induction have implications beyond that of eye research. In this
review, we focus on the early stages of lens development, during
which the lens-forming gene network is established. We highlight
the genes involved in this process and discuss the phenotypic
consequences that mutations in the individual components of this
network have on rodent and human eye development and diseases.
This review is structured around the regulation and function of the
transcription factor Foxe3, as mutations in this gene have been
shown to cause human and rodent lens diseases.
Lens induction: the tissues involved
The vertebrate lens is formed from the lateral surface ectoderm of
the head under the influence of the anterior neuroectoderm that is
destined to become the retina (Fig. 1A). Upon contacting the
evaginating optic vesicle, the surface ectoderm thickens and forms a
lens placode (Fig. 1B). During subsequent stages of development,
the lens placode invaginates and forms a lens vesicle (Fig. 1C,D).
The cells at the posterior of the vesicle begin to differentiate and
elongate to form the lens fiber cells (Fig. 1E). The lens fiber cells
eventually lose their nuclei and become transcriptionally silent. By
contrast, the cells at the anterior of the vesicle undergo only limited
differentiation and form the anterior lens epithelium. This epithelium
remains proliferatively active throughout the life of the individual,
slowly adding new lens fibers to the pre-existing lens.
The requirement for the presence of the optic vesicle in lens
induction is not entirely without controversy. Whereas in higher
vertebrates the requirement for signaling from the optic vesicle
during lens induction is well demonstrated (Brownell et al., 2000;
Kamachi et al., 1998; Mathers et al., 1997; Porter et al., 1997;
Swindell et al., 2006), in lower vertebrates, such as frog and salmon,
Department of Molecular and Cellular Biology, and Department of Molecular and
Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX 77030,
USA.
*Author for correspondence (e-mail: [email protected])
lens formation without the formation of the retina has been reported
(Mencl, 1903; Spemann, 1912). How the lens develops in these
species in the absence of the retina is not understood. The nature of
this problem can best be demonstrated by the example of lens
formation in the zebrafish retinal homeobox gene 3 (rx3; chokh)
mutant, which forms a lens without ever forming a retina (Loosli et
al., 2003). In zebrafish, rx3 is necessary for the morphogenesis of
the optic vesicle. Although it is true that the optic vesicle does not
form in rx3 mutants, a part of the neuroectoderm (brain) displays
retina-specific gene expression (Loosli et al., 2003). This gene
expression is likely to be responsible for the induction of lens
formation in this mutant. This example demonstrates the need for
molecular analyses of the processes involved in ‘retina-free’ lens
induction. Although there has been great progress in the analysis of
lens formation during the last decade, it is still not fully understood
how developmental processes and genes function during lens
development and disease. For this reason, the study of the function
and regulation of genes expressed during the early stages of lens
development is of great interest. As expected, many genes have
already been identified that are expressed during early lens
development, but most of them are also expressed in other tissues of
the embryo, without lenses forming at these locations. This
observation has led to the conclusion that interactions among several
gene products are necessary for the initiation of lens formation.
Foxe3 and lens development
One of the first genes to display lens-specific expression in the
mouse eye is the Fox gene Foxe3. Foxe3 encodes a DNA-binding
transcription factor that has an onset of expression that is
coincidental with the formation of the lens placode (Blixt et al.,
2000; Brownell et al., 2000). Foxe3 was initially isolated on the basis
of its similarity to the Xenopus gene Xlens1 (also called FoxE4),
which is the earliest specific marker of lens development in Xenopus
(Kenyon et al., 1999). In mouse, Foxe3 is initially expressed in the
undifferentiated lens placode, and later its expression persists in the
relatively undifferentiated anterior lens epithelium, but not in the
differentiating lens fiber cells. The first clues about the crucial
function of Foxe3 in lens development came from chromosomemapping experiments, which placed this gene on chromosome 4
(Blixt et al., 2000; Brownell et al., 2000), in the vicinity of the
dysgenetic lens (dyl) locus (Sanyal et al., 1986). Mice carrying the
dyl mutation display abnormal lens development (Fig. 2B).
Sequencing of Foxe3 from the dyl strain of mice revealed the
existence of two mutations in the DNA-binding domain of Foxe3,
which reduce the ability of the Foxe3 protein to interact with DNA
(Blixt et al., 2000; Brownell et al., 2000). In a dyl homozygous
mutant, this reduced capability of Foxe3 to bind to DNA results in
the formation of smaller lenses, in which the anterior lens epithelium
does not separate from the cornea (keratolenticular adhesion). Later
in development, some lens cells get extruded owing to intraocular
pressure, and the remaining lens develops a cataract (Sanyal and
Hawkins, 1979; Sanyal et al., 1986). Heterozygous dyl mice display
corneal and lenticular defects, with a variable degree of penetrance
(Ormestad et al., 2002).
DEVELOPMENT
The recent identification of a mutation in Foxe3 that causes
congenital primary aphakia in humans marks an important
milestone. Congenital primary aphakia is a rare developmental
disease in which the lens does not form. Previously, Foxe3 had
been shown to play a crucial role in vertebrate lens formation
and this gene is one of the earliest integrators of several
signaling pathways that cooperate to form a lens. In this review,
we highlight recent advances that have led to a better
understanding of the developmental processes and gene
regulatory networks involved in lens development and disease.
1456 REVIEW
Development 134 (8)
A
HSE NE
B
C
D
E
LF
R
OV
LP
LV
ALE
In mice with a targeted deletion of both alleles of Foxe3 (MedinaMartinez et al., 2005), the cells of the anterior lens epithelium cease
to proliferate prematurely and the lens is smaller, sometimes almost
absent (Fig. 2D). The anterior lens epithelium fails to separate from
the cornea (Fig. 2C), and the differentiating fiber cells do not lose
their nuclei; they also do not elongate properly. Eventually, severe
vacuolization takes place and a cataract develops. As a consequence
of abnormal lens development, the retina shrinks and displays
abnormal folding. Corneal dystrophy frequently accompanies this
condition.
Why is lens development abnormal without Foxe3
function?
The Foxe3 mutant lens undergoes several abnormal morphological
changes, such as a reduction in size, keratolenticular adhesion,
cataract formation and altered differentiation of fiber cells. To link
morphological changes to molecular events is a daunting task when
the mutated gene encodes a transcription factor, as its function might
affect the expression of hundreds of genes (Chauhan et al., 2002).
With this in mind, we will attempt to explain the morphological
changes that occur in lenses with mutated Foxe3, on the basis of
molecular changes that have been detected in the lenses of Foxe3
mutant mice.
One of the changes observed in mice with mutant or absent Foxe3
protein is the smaller size of the lens placode, which leads to a smaller
mature lens. In Foxe3 mouse mutants, the anterior lens epithelium
shows reduced proliferation, as measured by BrdU incorporation
(Blixt et al., 2000; Medina-Martinez et al., 2005). This reduced
proliferation might be partially due to the abnormal expression of the
cyclin-dependent kinase inhibitor Cdkn1c (Blixt et al., 2000). Cdkn1c
blocks cell cycle progression and is normally not expressed in the
anterior lens epithelium of the wild-type mouse lens. However, in
Foxe3 mutants, its expression extends into the posterior part of the
lens epithelium, which is typically the most active zone of
proliferation. As a result, the proliferation in this region is strongly
reduced. The initial cause of this ectopic expression of Cdkn1c
appears to be the deregulation of expression of Prox1, which is the
mouse homolog of the Drosophila homeobox gene prospero (Oliver
et al., 1993). Prox1 expression is barely detectable in the anterior lens
epithelium of the wild-type lens, which transcribes high levels of
Foxe3 mRNA. However, in Foxe3 mutants, high levels of Prox1
mRNA are present in the posterior part of the lens epithelium (Blixt
et al., 2000). This high level of Prox1 is presumably responsible for
the upregulation of Cdkn1c, as Prox1 seems to be the key regulator
of Cdkn1c expression (Wigle et al., 1999).
Although the most anterior epithelial cells are not affected by the
premature expression of Prox1, they do stop proliferating,
suggesting that another mechanism is involved in the control of
proliferation of anterior epithelial cells. This regulation of
proliferation might be mediated by the platelet-derived growth factor
alpha (Pdgf␣), which is secreted by the ciliary body, iris epithelium
and corneal endothelium. This growth factor is released into the
anterior chamber and binds to the platelet-derived growth factor
alpha receptor (Pdgfr␣), which is expressed in the lens epithelium.
Upon binding of Pdgf␣ to its receptor, proliferation is induced
(Reneker and Overbeek, 1996). In Foxe3 mutants, the expression of
Pdgfr␣ is strongly reduced (Blixt et al., 2000). This reduced
expression of Pdgfr␣ most likely contributes to the reduced
proliferation in the anterior lens epithelium.
Surprisingly, in zebrafish in which foxe3 expression has been
reduced by a foxe3 morpholino, proliferation in the lens, as
measured by the expression of proliferating cell nuclear antigen
(pcna), is increased rather than decreased (Shi et al., 2006).
However, as in mouse Foxe3 mutants, the size of the lens in zebrafish
morphants is smaller than in wild-type embryos. It is not known
whether the opposite effect of Foxe3 on proliferation in mouse and
zebrafish is a result of an evolutionary altered function, or a
discrepancy that has arisen from the use of different diagnostic
methods to measure cell proliferation.
Another abnormal feature of lenses in Foxe3 mouse mutants is the
lack of separation of the anterior lens epithelium from the cornea,
which might be due to the lack of apoptosis in the lens stalk. Cell
death by apoptosis has been implicated as a mechanism in the
separation of the lens from the cornea (Ozeki et al., 2001).
Alternatively, the lack of separation of the anterior lens epithelium
from the cornea might be due to the abnormal expression of cell
adhesion molecules, such as the N- and E-cadherins, in the anterior
lens epithelium. The published data on the expression of cadherins
and the apoptosis of the lens stalk in dyl mutants is limited (Blixt et
al., 2000) and cannot be easily used to determine if any of these two
processes is responsible for the lack of separation of the lens from
the cornea.
DEVELOPMENT
Fig. 1. Schematic of vertebrate lens development. (A) Morphogenesis of the lens begins when the evaginating optic vesicle (OV), which derives
from the neuroectoderm (NE, blue), contacts the head surface ectoderm (HSE, yellow). (B) Upon this contact, the HSE thickens and forms a lens
placode (LP). (C,D) The optic cup subsequently forms the retina (R) and the lens placode invaginates and forms a lens vesicle (LV). (E) Once the
vesicle is formed, the lens cells in the posterior half of the vesicle elongate and form the lens fiber cells (LF). By contrast, the cells in the anterior of
the lens vesicle remain as a monolayer and form the anterior lens epithelium (ALE). Modified with permission from Lovicu and McAvoy (Lovicu and
McAvoy, 2005).
Development 134 (8)
REVIEW 1457
Fig. 2. A comparison of wild-type and Foxe3 mutant mouse eyes.
(A) Hematoxylin-Eosin (HE)-stained coronal section of a P14 wild-type
mouse eye showing a lens stained in pink. (B) An HE-stained coronal
section of a P1 eye from a dyl mouse showing an abnormal small lens,
cornea and retina (blue). (C,D) Coronal sections of eyes from P14
Foxe3–/– mice showing abnormal features of the lens, cornea and
retina. Note the rudimentary lens (arrowed) in D. (E) Cerebral magnetic
resonance imaging (MRI) of a 3-year-old human subject with a mutated
FOXE3 gene, showing absence of the lens. (F) An HE-stained section
through the eye of a 3-month-old child with a mutated FOXE3 gene,
showing the absence of the lens (arrow). The asterisk indicates the
empty cavity, most likely corresponding to the vitreous. c, cornea; l,
lens; on, optic nerve; r, retina. A,C,D are reproduced with permission
from Medina-Martinez et al. (Medina-Martinez et al., 2005); B is from I.
Brownell and M.J., unpublished; E,F are reproduced with permission
from Valleix et al. (Valleix et al., 2006).
Somewhat later, during lens differentiation, another abnormal
feature becomes apparent in Foxe3 mouse mutants. The
differentiating lens fiber cells do not lose their nuclei, they do not
assume a fiber-like shape and the lens develops a cataract. The
loss of nuclei, which is typical of lens fiber differentiation, is
absent in Foxe3 mutants and can be explained by the involvement
of Foxe3 in the regulation of the DNase II-like acid DNase [Dlad;
also known as deoxyribonuclease II beta (Dnase2␤)]. This
nuclease is responsible for the degradation of the nuclear DNA
during lens differentiation. In its absence, the DNA is not
degraded and the nuclei are not lost (Nishimoto et al., 2003). In
Foxe3-null mice, there is a significant downregulation of Dlad. It
is likely that as a consequence of this Dlad downregulation, the
nuclei do not get eliminated in mutant lens cells (Medina-
FOXE3 and human disease
After the initial observations that mutations in Foxe3 cause abnormal
lens development in mice, it was quickly realized that the ocular
defects in Foxe3 mutant mice resembled conditions frequently
encountered in humans. The analysis of DNA from patients with
Peters’ anomaly (Peters, 1906; Smith and Velzeboer, 1975)
identified a frameshift mutation in FOXE3 as one of the causes of
this abnormal condition (Semina et al., 2001). Peters’ anomaly is a
congenital disease that frequently manifests as central corneal
opacity, keratolenticular adhesion and, sometimes, anterior polar
cataract. This condition can be caused by mutations in PAX6
(Hanson et al., 1994), PITX2 (Doward et al., 1999) or CYP1B1
(Vincent et al., 2006; Vincent et al., 2001), but in most cases the
genetic basis is unknown. Further evidence for the role of FOXE3 in
Peters’ anomaly was provided by Ormestad and colleagues
(Ormestad et al., 2002), who identified a heterozygous individual in
which a rare, non-conservative substitution in FOXE3 resulted in
Peters’ anomaly.
Finally, it was found recently that a mutation in FOXE3 in humans
is one cause of congenital primary aphakia (Fig. 2E,F) (Valleix et
al., 2006). Human aphakia is a rare congenital eye disorder in which
the lens is missing. In primary aphakia, lens formation does not take
place and the secondary ocular defects, including a complete aplasia
of the anterior segment of the eye, are considered to be the result of
the absence of the lens. In secondary aphakia, lens formation does
take place, but the lens degenerates and is resorbed perinatally. For
this reason, the ocular defects in secondary aphakia tend to be less
severe than in primary aphakia. The features of congenital primary
aphakia in humans, described by Valleix and co-workers (Valleix et
al., 2006), resemble the extreme phenotype of Foxe3-null mice, in
which only very small, undifferentiated lenses develop (Fig. 2D;
Medina-Martinez et al., 2005). The phenotype in humans appears to
be somewhat more pronounced, as lenses are totally absent and other
eye structures, including the iris, ciliary body and trabecular
meshwork, are missing. However, it is difficult to make a
generalization, as the data on congenital primary aphakia are based
on only one family. In addition, the direct comparison of human and
DEVELOPMENT
Martinez et al., 2005). Another contributing factor to the cataract
formation in Foxe3 mutants might be the altered expression of
␣A-crystallin. In the wild-type lens, lens fiber cells express high
levels of crystallins, which can represent more than 90% of the
total protein in the cell. ␣A-crystallin constitutes about 17% of the
total protein in the cell. Studies into crystallin structure and
regulation have provided some important insights into their
evolution, as well as into gene sharing in general. It was found that
crystallins are not lens-specific proteins, but rather are proteins
that are also utilized by other cells of the body, but for different
functions (Piatigorsky, 1998; Wistow and Piatigorsky, 1987). For
example, it was found that ␣A-crystallin is a small heat-shock
protein (Ingolia and Craig, 1982) that can act as a molecular
chaperone (Horwitz, 1992; Jakob et al., 1993). More recently,
analysis of the zebrafish mutant cloche, which develops a cataract,
revealed that a downregulation of ␣A-crystallin expression leads
to the insolubility of ␥-crystallin and to an opaque lens (Goishi et
al., 2006). In Foxe3 mutants, the transcription of ␣A-crystallin is
altered (Blixt et al., 2000; Brownell et al., 2000; Medina-Martinez
et al., 2005), raising the possibility that this misregulation of ␣Acrystallin expression leads to a reduced solubility of ␥-crystallin,
which might contribute to cataract formation.
The inability of lens fiber cells in Foxe3 mutants to assume the
fiber-like cell shape is unexplained at present.
mouse diseases is not a trivial task, as the phenotype of a disease in
mice sometimes varies according to the genetic background of the
strain (Blixt et al., 2006).
Upstream of Foxe3
Whereas mutations in Foxe3 cause severe abnormalities in lens
development, there are several genes that are expressed prior to
Foxe3 that are necessary for lens formation. Some of these genes are
expressed in head surface ectoderm, but also in other tissues. For
example, the homeobox-containing gene Pax6 is expressed during
early lens development, and mutations in this gene lead to eye
disorders, known as small eye (sey) syndrome in mice and rats
(Fujiwara et al., 1994; Hill et al., 1991), and aniridia and Peters’
anomaly in humans (Glaser et al., 1994; Hanson et al., 1994; Jordan
et al., 1992; Ton et al., 1991). However, Pax6 is not only expressed
in the superficial head ectoderm, from which the lens is derived, but
also in the neuroectoderm, from which the retina is derived. The
expression in the superficial head ectoderm seems to be crucial for
lens formation, as Pax6-deficient superficial head ectoderm does not
form a lens when transplanted onto a wild-type optic vesicle
(Fujiwara et al., 1994). Furthermore, the lens-specific ablation of
Pax6 expression in mice using a floxed allele of Pax6 crossed to a
lens-specific Le-Cre, results in a lack of lens formation (AsheryPadan et al., 2000). Whether Pax6-deficient neuroectoderm is able
to induce lens formation is not entirely clear. Although Fujiwara and
colleagues (Fujiwara et al., 1994) showed that the wild-type
ectoderm can induce lens formation when transplanted on the Pax6deficient neuroectoderm, they also observed the first morphological
signs of lens induction in the wild-type head ectoderm before the
transplantation was performed. Therefore, it is not certain whether
lens induction takes place in the absence of Pax6 in the
neuroectoderm. A genetic ablation of Pax6 using Pax6flox and a
retinal neuroectoderm-specific Cre, such as Rx-Cre (Swindell et al.,
2006), should provide a definitive answer to this question.
Furthermore, it is also unclear to what degree the Pax6 function in
the neuroectoderm is required for the normal differentiation of the
lens. The rat recombination experiments of Fujiwara and colleagues
(Fujiwara et al., 1994) showed that a significant degree of lens
differentiation takes place in the absence of Pax6 expression in the
neuroectoderm. However, in chick in which Pax6 function in the
neuroectoderm was eliminated by the injection of either a Pax6specific morpholino or Pax6 dominant-negative construct, the
differentiation of the lens did not proceed normally (Canto-Soler and
Adler, 2006; Reza and Yasuda, 2004).
Interestingly, mutations in PAX6, as in FOXE3, cause Peters’
anomaly (Hanson et al., 1994). The explanation for this phenomenon
is that Foxe3 appears to be regulated by Pax6 (Blixt et al., 2006;
Brownell et al., 2000; Dimanlig et al., 2001), and in humans, as far
as the lens is concerned, mutations in both genes seem to have a very
similar clinical manifestation. Pax6 is involved in a complex
regulatory network. Pax6 is autoregulated by itself (Aota et al.,
2003), as well as being regulated by the Six3 and Meis
homeoproteins, which are required for lens formation (Liu et al.,
2006; Zhang et al., 2002). Important regulatory partners of Pax6 are
the Sox proteins, which have been implicated in lens induction
(Donner et al., 2006a; Kamachi et al., 1998; Kamachi et al., 2001;
Kondoh et al., 2004; Koster et al., 2000). Sox2 in combination with
Oct-1 (Pou2f1 – Mouse Genome Informatics) protein control the
maintenance of Pax6 expression, and through this activity they
control lens formation (Donner et al., 2006a). Several other genes
have been suggested to be upstream regulators of Foxe3, including
Mab21/1, a member of the Mab gene family, which is also essential
Development 134 (8)
for the development of the lens placode in mouse (Yamada et al.,
2003). Mab21/1 function is necessary for Foxe3 expression (Yamada
et al., 2003). Furthermore, the Smad-binding zinc-finger
homeodomain transcription factor Sip1 is also essential for the
activation of Foxe3 expression (Yoshimoto et al., 2005). During the
activation of Foxe3, Sip1 interacts with Smad8 (also known as
Smad9 in mouse), which is one of the mediators of Bmp4 signaling
in vertebrates. The Bmp4 pathway has previously been
demonstrated to be crucial for lens formation (Furuta and Hogan,
1998). Although a complete picture of the interactions of the
different transcription factors cannot be drawn at this point, some
regulatory interactions have been depicted in Fig. 3.
In addition to transcription factors, several signaling pathways
have been implicated in lens formation, including the Wnt signaling
pathway. This signaling pathway needs to be integrated into any
model of lens development owing to the observation that when ␤catenin function is eliminated in the Pax6-expressing area in the
presumptive lens ectoderm, ectopic lens-like structures develop in
this location (Smith et al., 2005). This suggests that the elimination
of ␤-catenin signaling is crucial for lens formation. Consistent with
this observation, ␤-catenin loss-of-function in the lens placode does
not alter lens fate (Smith et al., 2005), presumably because the ␤catenin signaling was already eliminated in this tissue. All of these
observations indicate that several independent pathways are
integrated into a network responsible for the formation of a lens.
How this integration of several signaling pathways works at the
molecular level is not yet fully understood. A possible mechanism
for the establishment of lens-specific expression was recently
demonstrated by Yang and co-workers, through their studies of the
␣A-crystallin gene (Cryaa) (Yang et al., 2006). Pax6 initially binds
the cis-regulatory elements of Cryaa. This binding attracts Brg1
(Smarca4 – Mouse Genome Informatics), a murine homolog of the
Drosophila brahma gene (Khavari et al., 1993; Randazzo et al.,
1994). Brg1 is a catalytic subunit of SWI/SNF, an evolutionary
conserved class of chromatin remodeling factors (Mohrmann and
Verrijzer, 2005). The partially remodeled chromatin becomes
accessible to additional transcription factors, such as c-Maf (Maf –
Mouse Genome Informatics) (Ishibashi and Yasuda, 2001; Yoshida
et al., 1997), which facilitate the activity of further chromatin
remodeling enzymes to fully open the Cryaa promoter to additional
transcriptional regulators.
Pre-placodal gene expression
Several transcriptional regulators that are essential for lens
formation, such as Pax6, Six3 and Sox2, are not only expressed in
the lens placode, but also in other placodal structures. Because of
their expression in multiple placodal structures, several authors have
suggested that during early development a uniform, U-shaped, preplacodal field is induced that surrounds the anterior neuroectoderm
(Bailey et al., 2006; Baker and Bronner-Fraser, 2001; Donner et al.,
2006b; Jacobson, 1966; Kenyon et al., 1999; Schlosser and Ahrens,
2004; Torres and Giraldez, 1998). Only later is this pre-placodal
field divided into individual placodes. Gene expression in the Ushaped field in the anterior non-neural ectoderm can be
demonstrated by the example of Xlens1, the Xenopus functional
homolog of Foxe3. During neurulation, Xlens1 has a U-shaped
expression domain, with the strongest expression in the middle of
the field (Fig. 4A; our unpublished observations). Later in
development, its expression diminishes in the middle and becomes
more prominent in the presumptive lens placodes (Fig. 4B) (Kenyon
et al., 1999). Several genes display a similar U-shaped expression
pattern, with the field varying slightly in size and location, indicating
DEVELOPMENT
1458 REVIEW
Fig. 3. Regulatory interactions during lens formation in the head
surface ectoderm and lens. (A) Schematic depicting selected
transcription factors important for lens formation that are expressed in
the mouse head surface ectoderm. These interactions help specify the
activation of Foxe3 in the lens placode. (B) Roles of Foxe3 in the
development and differentiation of the lens (orange). Feedback loops
are not depicted here and arrows between genes do not necessarily
imply direct regulatory interactions.
that some regionalization of this domain already takes place during
gastrulation (for a review, see Schlosser, 2006). This pre-placodal
field initially encompasses a large part of the anterior, lateral and
ventral head surface ectoderm and gives rise to several placodal and
non-placodal structures. The establishment of this field was
suggested to be the first step towards the establishment of lens
competence in Xenopus (Servetnick and Grainger, 1991). A part of
this field is called the pre-lens ectoderm (Ashery-Padan et al., 2000;
Schlosser, 2006; Schlosser and Ahrens, 2004; Williams et al., 1998).
The central part of the pre-lens ectoderm forms the lens placode,
whereas the lateral parts of this field form non-placodal structures.
It was recently proposed, based on experiments in chick, that the
entire pre-placodal region is initially specified to form a lens (Bailey
et al., 2006), and therefore it is not clear how the pre-placodal field
differs from the pre-lens ectoderm in terms of lens competence.
Whether the model of lens induction proposed by Bailey and
colleagues applies to mammals is uncertain, as it contradicts data
from mouse experiments. There is substantial evidence in mice that
the optic vesicle is necessary for lens induction and the initiation of
lens-specific gene expression (Faber et al., 2001; Furuta and Hogan,
1998; Wawersik et al., 1999). Furthermore, mice deficient in Rx (Rax
– Mouse Genome Informatics) function, which have no retinal
REVIEW 1459
Fig. 4. Expression of Xlens1 and Foxe3 during lens formation in
Xenopus and mouse. (A) Anterior view of Xlens1 expression in the
U-shaped region of Xenopus neurula (our unpublished observation).
(B) Expression of Xlens1 in the lens placodes of a Xenopus tadpole
(Kenyon et al., 1999). (C) The earliest expression of Foxe3 in the lens
placode of an E9.0 mouse embryos (arrow). Reproduced with
permission from Blixt et al. (Blixt et al., 2000). (D) Expression of Foxe3 in
an E12 mouse embryo. Reproduced with permission from Brownell et
al. (Brownell et al., 2000).
neuroectoderm, display no lens-specific gene expression and form
no lenses (Bailey et al., 2004; Brownell et al., 2000; Mathers et al.,
1997; Zhang et al., 2000; Zilinski et al., 2004). In these mice that
lack retina and lens, other placodal structures form normally and the
non-placodal structures arising from the ‘pre-lens ectoderm’ also
form normally (E. Swindell and M.J., unpublished). These
experiments clearly show that gene expression in the head surface
ectoderm without the input of Rx-expressing retinal cells is not
sufficient to induce the lens. Therefore, changes in gene expression
orchestrated by the optic vesicle appear to be essential for the
establishment of lens fate in mice. For this reason, an important task
for the future will be to establish the gene expression pattern in the
head surface ectoderm in the absence of the retina, and compare it
with that in the presence of the retina. Only then will we be able to
distinguish changes in gene expression that are due to general
cranio-facial patterning from those specifically needed to make a
lens.
There are several possibilities to explain these discrepancies and
one of them is to postulate that evolutionary changes have occurred
in the specification of placodal structures. One piece of evidence
supporting this hypothesis is the expression pattern of Foxe3.
Whereas Xlens1 is initially expressed in a U-shaped field that
surrounds the anterior neural ectoderm (Fig. 4A) (Kenyon et al.,
1999; Zilinski et al., 2004), Foxe3 in mice is not expressed in a Ushaped domain. From the earliest onset, Foxe3 is expressed in two
distinctly separate fields (Fig. 4C) (Blixt et al., 2000), indicating that
different mechanisms for lens specification exist in Xenopus and
mouse. Although the differences in the expression patterns of these
DEVELOPMENT
Development 134 (8)
two Fox genes are striking, the significance of the Xlens1 U-shaped
expression with respect to lens formation is not understood. Since
cell fate experiments were not performed on the cells in the Ushaped Xlens1 expression area, it is not clear whether these cells
generate all or most of the cells of the lens placode. It is possible that
the expression of Xlens1 in the U-shaped region and in the lens
placodes reflect two independent processes. It is also possible that
the early U-shaped expression of certain genes is not necessary for
lens formation. It is important to remember that even though the
expression of Xlens1 or Foxe3 in the eye is lens-specific, these genes
are expressed in other tissues in the embryo that do not form a lens
(Blixt et al., 2000; Brownell et al., 2000; Yu et al., 2002). For this
reason, it is not necessarily valid to use the expression of a certain
gene as an indicator of the formation of a specific structure.
Although additional experiments will be needed to determine the
role of this early U-shaped expression in lens formation, it is
nonetheless certain that a lens placode eventually develops that has
a different appearance and a different gene expression profile than
the surrounding surface ectoderm or other placodal structures. The
question of which developmental steps make the lens cells become
different from their neighbors is central to lens research, but the
answer to this question remains unknown.
As mentioned previously, it appears that the mechanism of lens
induction is not wholly conserved in all vertebrate species. To find
evolutionary changes in lens induction might not be entirely
surprising, as lens differentiation in various species displays
significant variations. For example, whereas in most species the lens
undergoes invagination, in zebrafish the lens is generated through
delamination (Soules and Link, 2005). Furthermore, different
mechanisms of lens suture formation in different species indicate
that the lens-forming network has an inherent flexibility to produce
correct lenses in each species (Kuszak et al., 2004). Therefore,
although most of the components in lens formation are conserved
(Donner et al., 2006b), their interactions might be modified to
varying degrees in different species. As such, the use of a single
model to explain lens formation in all species might be
counterproductive for the better understanding of lens formation in
each separate species.
Ectopic lens formation
Although most of the evidence suggests that a specific gene network
is required to initiate lens development, gene networks present in
other tissues can be manipulated to form a lens. For example,
overexpression of Pax6 can lead to ectopic lens formation in
Xenopus (Chow et al., 1999). However, Pax6 can induce lens
formation more easily in the head ectoderm than in the trunk
ectoderm of Xenopus (Chow et al., 1999), demonstrating that some
gene networks can be more easily modified to form a lens than
others. The ectopic expression of Sox3 can induce ectopic lens
formation in the head surface ectoderm of Medaka (Koster et al.,
2000), and ectopic expression of six3, which is normally expressed
in the lens placode, leads to the formation of a lens in the ear placode
of zebrafish (Oliver et al., 1996). The molecular process of changing
one placodal structure into another can be demonstrated by the
formation of the zebrafish anterior pituitary gland. The anterior
pituitary gland is a placode-derived structure that, in its early stages,
seems to have the same gene expression pattern as the lens placode.
This common placodal area expresses the transcription factor pitx3
and can form either pituitary or lens (Dutta et al., 2005; Shi et al.,
2005; Zilinski et al., 2005). To form the anterior pituitary gland,
hedgehog signaling is required in the placodal region. In the
zebrafish mutant smoothened, hedgehog signals cannot be
Development 134 (8)
transduced, and the pituitary precursors form an ectopic lens instead
of a pituitary (Dutta et al., 2005). If sonic hedgehog (shh) is
overexpressed in the lens precursors, they begin to express genes
characteristic of pituitary cells (Dutta et al., 2005). Although the
ability to induce ectopic lens formation is intriguing, the ectopic
induction of lens-specific gene expression might not follow the
normal sequence of events involved in lens formation. For example,
the Maf gene family plays an important role in lens formation in
several vertebrate species (Ishibashi and Yasuda, 2001; Reza et al.,
2002). In Xenopus, overexpression of XmafB, a member of the Maf
gene family, in animal caps leads to the activation of Xlens1
(Ishibashi and Yasuda, 2001). However, the analysis of gene
expression in intact embryos shows that XmafB expression in the
head ectoderm normally starts several hours after Xlens1 is activated
(Ishibashi and Yasuda, 2001; Kenyon et al., 1999). Therefore, the
activation of Xlens1 probably does not require XmafB during normal
development. This observation suggests that the process of ectopic
tissue formation can utilize an alternative mechanism for tissue
specification. For example, feedback loops, which might play a
minor role during normal development, could be used to activate
genes that are normally upstream in the regulatory cascade. An
interesting example of ectopic lens formation was recently described
in chick embryos, in which the neural crest cells were surgically
removed from the embryo (Bailey et al., 2006). In these embryos,
ectopic lenses develop posterior to the endogenous lenses. This is
presumably because the neural crest cells play an inhibitory role in
lens formation and, during their absence, regions of head surface
ectoderm form lenses that would normally have been prevented from
doing so (Bailey et al., 2006).
A prime example of the differential pliability of gene networks is
the different ability of species to regenerate a lens. Whereas the lens
will readily regenerate in some amphibians (Eguchi, 1967; Eguchi,
1988; Stone, 1953; Stone, 1967; Wolf, 1895), this ability is much
more limited in mammals. In newts, the dorsal iris pigment
epithelium can be induced to regenerate a lens by lentectomy (Del
Rio-Tsonis et al., 1998; Madhavan et al., 2006; Tsonis et al., 2004).
This process of lens regeneration seems to be true
transdifferentiation, as fully differentiated iris cells dedifferentiate
and then redifferentiate into lens cells (Del Rio-Tsonis and Tsonis,
2003). To what degree the process of lens regeneration is similar to
lens induction during early development is not entirely clear at
present. Since a lens forms during lens regeneration, many of the
differentiation products are shared in these two processes. However,
there must certainly also be differences, as the iris cells must
dedifferentiate before they start the lens differentiation program. One
unanswered question is to what degree must the iris cells
dedifferentiate before they can start the lens-forming process? Must
they acquire the same state as the head ectoderm prior to lens
induction, or is there a shortcut that the dedifferentiating iris cells
use to make a lens? The published evidence suggests that although
there are many similarities between the temporo-spatial expression
of genes during lens induction and regeneration, there are also
differences, indicating that the two processes are not identical
(Mizuno et al., 2002; Mizuno et al., 1999). One intriguing possibility
is that during transdifferentiation the cells assume a state that is
identical, or very similar, to the state of embryonic stem (ES) cells.
While this possibility is under investigation, it has already been
demonstrated that primate ES cells can be directed to form Pax6and ␣A-crystallin-expressing lentoid bodies after treatment with
FGF2 (Ooto et al., 2003). FGF2 triggers lens regeneration in newt
(Hayashi et al., 2004), and FGF molecules and their receptors are
known to play a role in different aspects of lens formation (for
DEVELOPMENT
1460 REVIEW
reviews, see Lovicu and McAvoy, 2005; Robinson, 2006). The
ability to use ES cells to generate lentoid bodies can be exploited in
experiments designed to better understand lens development.
Perspectives
Recent research has led to the identification of developmental
processes and genes that have a role in lens formation. This research
has helped to identify causes of human lens diseases and has opened
new avenues for possible therapeutic approaches. Foxe3 has been
identified as one of the key players in lens development. How this
early transcription factor modulates aspects of lens development and
differentiation is not fully understood. For example, there are only a
few known targets of Foxe3, and it is not known whether Foxe3
directly regulates these targets. A search for additional targets of
Foxe3 is warranted. The identification of a full complement of genes
that are directly regulated by Foxe3 would provide a good starting
point to assemble the gene network in which Foxe3 plays a central
role.
The developmental processes and gene interactions upstream of
Foxe3 are also poorly understood. Disparities have been reported in
lens induction between different species and one of the challenges
for the future is to determine which differences are due to
evolutionary changes and which are due to the methodologies used
to study lens induction. One of the problems associated with
comparing lens induction is that the so-called pre-placodal region is
not well defined in most species. Whereas in Xenopus there is a
fairly detailed map of gene expression in this region (Schlosser,
2006), in mice, the expression data for this area are rudimentary at
best. In addition, the function and significance of gene expression in
the pre-placodal region are not clear. For example, the expression of
Pax6 in the head surface ectoderm varies at different stages of
development. In some stages, it encompasses practically the entire
head. Several placodal and non-placodal structures develop from the
Pax6 expression area. Analysis of lens formation does demonstrate
the need for Pax6 expression in the head surface ectoderm, but it
remains to be demonstrated that this expression is a step specifically
directed towards lens formation. In many recent developmental lens
studies, changes in gene expression in the head ectoderm have been
monitored as a measure of the competence of this ectoderm to form
a lens. Although this lens-centric view helps to identify gene
expression in the head ectoderm that is necessary for lens formation,
it does not distinguish between changes in gene expression that are
due to general cranio-facial patterning from those changes that are
specifically made to generate a lens. If we designate all
developmental processes necessary for lens formation as part of the
lens-forming cascade, will we not have to declare that fertilization
itself is a part of this cascade?
In our opinion, the important task for the future will be to establish
the gene expression pattern in the head surface ectoderm in the
absence of the retina, and compare it with that in the presence of the
retina. Only then we will be able to distinguish changes in gene
expression that are due to general cranio-facial patterning from those
specifically made to induce lens formation.
Several other related questions remain unanswered. For example,
is the early pre-placodal region simply the anterior and lateral head
surface ectoderm from which some placodal and some non-placodal
structures of the head are derived? Is the complex and overlapping
gene expression in the early pre-placodal region simply reflecting
the fact that different signaling sources in the head neuroectoderm
are very close to each other during gastrulation? Is the progressive
regionalization of gene expression in the head surface ectoderm
simply reflecting the progressive differentiation and morphogenesis
REVIEW 1461
of the neural tube? Is the early pre-placodal head ectoderm in other
species specified to form a lens, as suggested by in vitro experiments
in chick? What is the difference between the pre-placodal ectoderm
and the pre-lens ectoderm?
In summary, although many of the important questions in lens
development and regeneration remain to be answered, we have
clearly reached a stage at which developmental lens research is not
only improving our molecular perspective on the initial stages of
lens induction, but also contributing to a better understanding of lens
diseases.
We thank several esteemed colleagues for their suggestions, Drs Paul
Overbeek and Eric Swindell for critical reading of the manuscript, and the
anonymous reviewers for their helpful comments.
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DEVELOPMENT
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