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First published online 7 March 2007
doi: 10.1242/dev.000117
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Review |
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: jamrich{at}bcm.tmc.edu)
SUMMARY
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.
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, 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 chromosome-mapping
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).
In mice with a targeted deletion of both alleles of Foxe3
(Medina-Martinez 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.
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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.
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
(Dnase2ß)]. 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-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 A-crystallin
expression leads to a reduced solubility of -crystallin, which might
contribute to cataract formation.
|
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 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
(Ashery-Padan 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
Pax6-deficient 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 Pax6-specific 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 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 ß-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 ß-catenin signaling is crucial for lens
formation. Consistent with this observation, ß-catenin loss-of-function
in the lens placode does not alter lens fate
(Smith et al., 2005),
presumably because the ß-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, pre-placodal 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 U-shaped 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 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 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.
|
|
; Zilinski et al.,
2004), Foxe3 in mice is not expressed in a U-shaped
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 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
U-shaped 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 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 Pax6- and 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 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 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.
ACKNOWLEDGMENTS
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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