Download Genetic regulation of vertebrate eye development

Clin Genet 2014: 86: 453–460
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© 2014 John Wiley & Sons A/S.
Published by John Wiley & Sons Ltd
CLINICAL GENETICS
doi: 10.1111/cge.12493
Developmental Biology: Frontiers for Clinical Genetics
Section Editors:
Jacques L. Michaud, e-mail: [email protected]
Bruno Reversade, e-mail: [email protected]
Genetic regulation of vertebrate eye
development
Zagozewski J.L., Zhang Q., Eisenstat D.D. Genetic regulation of vertebrate
eye development.
Clin Genet 2014: 86: 453–460. © John Wiley & Sons A/S. Published by
John Wiley & Sons Ltd, 2014
Eye development is a complex and highly regulated process that consists of
several overlapping stages: (i) specification then splitting of the eye field
from the developing forebrain; (ii) genesis and patterning of the optic
vesicle; (iii) regionalization of the optic cup into neural retina and retina
pigment epithelium; and (iv) specification and differentiation of all seven
retinal cell types that develop from a pool of retinal progenitor cells in a
precise temporal and spatial manner: retinal ganglion cells, horizontal cells,
cone photoreceptors, amacrine cells, bipolar cells, rod photoreceptors and
Müller glia. Genetic regulation of the stages of eye development includes
both extrinsic (such as morphogens, growth factors) and intrinsic factors
(primarily transcription factors of the homeobox and basic helix-loop helix
families). In the following review, we will provide an overview of the stages
of eye development highlighting the role of several important transcription
factors in both normal developmental processes and in inherited human eye
diseases.
Conflict of interest
None to declare.
J.L. Zagozewskia ,
Q. Zhangb
and D.D. Eisenstata,c,d
a Department of Medical Genetics,
University of Alberta, Edmonton, Alberta,
Canada, b Department of Human
Anatomy and Cell Science, University of
Manitoba, Winnipeg, Manitoba, Canada,
c Department of Biochemistry and
Medical Genetics, University of Manitoba,
Winnipeg, Manitoba, Canada, and
d Department of Pediatrics, University of
Alberta, Edmonton, Alberta, Canada
Key words: bHLH genes – eye
malformations – genetic eye diseases –
homeobox genes – retina development
– transcription factor
Corresponding author: Professor
David D. Eisenstat, MD, MA, FRCPC,
Departments of Pediatrics and Medical
Genetics, Room 8-43B Medical
Sciences Building, University of Alberta,
Edmonton AB T6G 2H7, Canada.
Tel.:780-492-9738;
fax: 780-492-1998;
e-mail: [email protected]
Received 30 June 2014, revised and
accepted for publication 20 August
2014
Vertebrate eye development is a complex process
regulated by intrinsic and extrinsic factors that work
in concert to specify an area of the forebrain as the
prospective eye field (EF), and then produce the neural
retina (NR). Their importance is shown in the ocular abnormalities that result from inherited mutations
(Table 1). Eye development begins at the late gastrula
stage when the EF is organized and bilaterally separated
in the neural plate (1, 2). At embryonic day (E) 8.5, the
optic vesicles (OVs) appear and evaginate laterally from
the forebrain, growing towards the overlying surface
ectoderm (Fig. 1a, Table 2) (3). As the OV comes in
close contact with the surface ectoderm, the surface
ectoderm thickens into the lens placode (LP). Then, the
OV and the LP invaginate, forming the optic cup (OC)
and the lens (Fig. 1b,c). The OC consists of two layers:
the retinal pigment epithelium (RPE) and the NR. The
NR develops further into the mature trilaminated retina
(Fig. 1d). In this review, we highlight the genetic mechanisms integral to eye development, with an emphasis on
the NR and on the role of basic helix-loop-helix (bHLH)
and homeobox gene transcription factors.
453
Zagozewski et al.
Table 1. Transcription factors mutated in ocular diseases
Transcription factor
Disease(s)
Crx
Cone-rod dystrophy
Leber congenital amaurosis
Retinitis pigmentosa
Microphthalmia
Aniridia
Ocular coloboma
Coloboma of optic nerve
Microphthalmia
Holoprosencephaly
Microphthalmia with cataract
Microphthalmia
Micropththalmia
Micropththlamia with coloboma
Nrl
Otx2
Pax6
Rax
Six3
Six6
Vax1
Vsx2
Phenotype MIM number
Gene MIM number
120970
613829
613750
610125
106210
120200
120430
611038
157170
212550
614402
610093
610092
602225
602225
162080
600037
607108
607108
607108
601881
603714
606326
604294
142993
142993
Fig. 1. Overview of vertebrate eye development. The OVs are the first visible structures of the vertebrate eye. The OVs evaginate from the midline of
the forebrain towards the overlying SE (a). Once OV contact is made with the thickened SE, which is now the LP, invagination of the OV and the LP
develop into the OC and the LV, respectively (b). The OC is divided into the NR and the RPE (c). The NR is further specified into six distinct neural
cell types: RGC (purple), AC (orange), BC (green), HC (light blue), cone PR (red) and rod PR (dark blue) and one glial cell (not shown). The retina
is organized into three cellular layers including the GCL, the INL and the ONL. Synaptic connections between the cellular layers are maintained in
the IPL and the OPL (d). GCL, ganglion cell layer; INL, inner nuclear layer; IPL, inner plexiform layer; LP, lens placode; LV, lens vesicle; NR, neural
retina; OC, optic cup; OV, optic vesicle; SE, surface ectoderm.
Eye field specification
The eyes are an extension of the developing forebrain
with EF specification preceded by neural induction and
patterning. Graded Wnt signalling is required to establish
anterior–posterior (A–P) polarity in the developing forebrain with increased Wnt signalling promoting posterior neural fates (4–6). Wnt mutants have reduced/absent
eyes and telencephalon, while the diencephalon expands
anteriorly (7).
454
In the anterior neural plate, the EF is specified by
the coordinated expression of the EF transcription factors (EFTFs). EFTFs have been best studied in Xenopus
laevis and include Rx1/Rax, Pax6, Six3, Lhx2, tll/Tlx,
Optx2/Six6 and ET/Tbx3 (8). Loss of function of individual EFTFs, including Rax, Pax6, Six3 and Lhx2, leads
to abnormal or absent eyes, showing their importance
in early eye development (9–12). In humans, RAX and
PAX6 mutations result in anophthalmia and aniridia,
Review of eye development
Table 2. Key developmental stages in vertebrate eye development (3)
Eye developmental
stage
Days gestation
(human)
Embryonic age
(in days) (mouse)
<22
22
28
32
33
E8.0
E8.5
E9.5
E10.0
E11.5
Eye field specification
OV Evagination
LP formation
OV and LP invagination
OC, start of retinal
neurogenesis
respectively (13, 14). EFTFs are necessary and also sufficient for eye development. Overexpression of individual
EFTFs including Pax6, Rx1, Pax6 and Six3, or an EFTF
‘cocktail’ can induce ectopic eye formation (8, 10, 15,
16). Otx2 plays a permissive role in EF specification.
Otx2 is first required for forebrain specification, which
is subsequently competent to specify the EF by EFTF
expression. As a result, Otx2 does not directly induce
EFTF expression (8).
Splitting the eye field
Two separate and identical eyes are formed following
establishment of the midline and splitting of the EF into
two lateral components. Failure of EF splitting results in
cyclopia. Sonic hedgehog (Shh) signalling is critical for
midline establishment. Mutant mice lacking Shh from
the prechordal plate mesoderm fail to establish the ventral midline and split the EF, producing a single midline eye and holoprosencephaly (17). Shh mutants fail
to upregulate Pax2, which marks optic stalk (OS) cells.
Six3, an EFTF, regulates the expression of Shh in the
developing forebrain and is associated with holoprosencephaly (11, 18, 19). Mutations in an upstream Shh
enhancer or in the SIX3 homeodomain reduce or abolish binding affinity of SIX3 for the enhancer element,
decreasing Shh signalling (20).
Optic vesicle development
Optic vesicle evagination
Following EF bisection, bilateral OVs form by evagination of the ventral forebrain neuroepithelium towards the
overlying surface ectoderm. Rax mutations in humans,
mice and zebrafish have no eyes, showing the importance of the homeobox gene Rax in early eye development (9, 14, 21–23). Rax (rx3 in zebrafish) mutants fail
to develop OVs (9, 21, 22). In zebrafish, expansion and
lateral evagination of the OVs from the forebrain are
driven by lateral migration of rx3 positive retinal progenitor cells (RPCs) (24). rx3−/− mutant RPC cells converge
at the midline without lateral migration, highlighting the
importance of rx3 in establishing OV outgrowth; rx3 controls expression of the cell adhesion molecule, nlcam,
and the chemokine signalling receptor, cxcr4a, providing some insight into targets of rx3 essential for enabling
OV lateral evagination (25, 26).
Optic vesicle patterning
As the OV evaginates, it is patterned along both the
dorsal–ventral (D–V) and the proximal–distal (P–D)
axes. Shh signalling from the ventral midline is necessary
for axial patterning. In D–V patterning, Shh establishes
ventral identity in the OV. Shh drives expression of
the ventralizing homeodomain transcription factors Vax1
and Vax2 (27, 28). Overexpression of Shh expands
Vax gene expression into the dorsal OV. Conversely,
Vax induction fails in the absence of Shh signalling.
In early optic development (E9.5), corresponding to
the OV stage, Vax1 and Vax2 expression co-localize
in the presumptive ventral OS and NR boundary (29,
30). Following invagination of the OV to initiate OC
formation (E10.5), Vax1 expression is restricted to the
OS (29, 31, 32) while Vax2 expression localizes to the
ventral NR of the OC (29, 33, 34). Retinal ganglion cell
(RGC) projections from Vax2 null mice are dorsalized
(34). Vax1/Vax2 double mutants have a severe dorsalized
eye phenotype where the ventral OS transforms into NR
(29). The expanded NR domain of the Vax1/Vax2 double
mutant expresses the RPC marker, Pax6 at the expense of
Pax2+ cells of the ventral OS, showing the requirement
for Pax6 in OV ventralization (29). Vax1 null mice have
axonal path-finding defects and coloboma whereas axial
patterning is largely unaffected (31).
In addition to its role in D–V patterning, Shh is also
critical for P–D OV patterning. As described, Pax2 and
Pax6 expression demarcate the proximal OS (35, 36) and
the distal OC (37, 38), respectively. Ectopic Shh activity
expands the Pax2 expression domain distally with a
corresponding decrease in Pax6+ cells in the distal OV
(39, 40). In addition, Pax2 and Pax6 repress each other
to maintain the P–D OS/OC boundary. Pax6 mutation
in the OV (E9.5) leads to an expanded domain of Pax2
expression into the OC primordia (41). Conversely, Pax6
expression extends into the ventral OS of Pax2 mutant
OVs (41).
Dorsal identity of the OV requires bone morphogenetic
protein 4 (BMP4), of the transforming growth factor
beta (TGFβ) family. BMP4 induces Tbx5 expression in
the dorsal OV (27, 42, 43). Overexpression of BMP4
results in ventrally expanded Tbx5 expression at the
expense of Vax gene expression, which is normally
localized to the ventral OV as described above (27, 42,
43). Mis-expression of Tbx5 in ventral OVs represses
Vax expression, resulting in aberrant projection of RGC
axons (42).
The LIM homeodomain transcription factor, Lhx2, also
patterns the developing OV. Lhx2 mutant mice are anophthalmic (12, 44, 45). However, human anophthalmia
resulting from LHX2 mutations has not been reported.
Without Lhx2, eye development arrests prior to the OV
to OC transition (12, 44, 45). In the arrested vesicles,
D–V patterning defects are evident as D–V determinants, Tbx5 and Vax2, are not upregulated or maintained
in the absence of Lhx2, respectively (44). In addition,
BMP signalling is not maintained in mutant OVs. Collectively, these observations highlight a critical role for
Lhx2 in D–V patterning.
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Zagozewski et al.
Optic cup stage
Regionalization of the neural retina and the retinal pigment
epithelium
Regionalization of the OV into NR and the RPE occurs
concurrently with D–V/P–D patterning along the evaginating OV. Invagination of the OV following contact with
the surface ectoderm initiates formation of the OC. The
outer layer of the OC gives rise to the RPE while the
inner layer develops into the NR. The prospective NR is
derived from the distal/ventral OV adjacent to the surface
ectoderm. The prospective RPE is specified by TGFβ
signalling from the extraocular mesenchyme (46, 47).
In the mouse, TGFβ signalling induces the expression
of the bHLH transcription factor, Mitf , and the homeodomain transcription factor, Otx2 in the distal OV. As
the OV approaches the surface ectoderm, Vsx2 expression initiated from surface ectoderm signals (see below)
represses Mitf , allowing the distal OV to develop into
NR. The Wnt pathway plays a role in both specification
and maintenance of RPE (48, 49). Loss of β-catenin at
the OV stage results in failed Mitf and Otx2 upregulation in the prospective RPE domain while the NR marker,
Vsx2 (formerly Chx10) expands dorsally into this domain
(49). Eye development in these mutants halts prior to
OC formation producing anophthalmic mice. At the OC
stage, β-catenin mutants fail to maintain Mitf and Otx2
in the OC, inducing ectopic NR at the expense of RPE.
Hence, β-catenin is essential to specify and to maintain
RPE identity in the OC (48).
Mitf and Otx2 bind to and activate genes required
for RPE differentiation including QNR71, Tyr, Trp1
and Trp2 (50, 51). Loss of function of Mitf or Otx2
results in ectopic NR formation with upregulation of
NR-specific markers at the expense of RPE, showing the
importance of these transcription factors for specification
and differentiation of the RPE, and restriction of NR
formation (52–55).
Fibroblast growth factor (FGF) signalling expressed
from the surface ectoderm overlying the OV specifies
the distal/ventral OV as NR. Addition of FGF2 to cultured OVs transforms prospective RPE into NR (56).
Conversely, blocking FGF2 in OV blocks specification of
NR tissue. FGF1 and FGF2 are highly expressed in the
surface ectoderm (57). Removing the surface ectoderm
from OV explants fails to maintain NR Vsx2 expression,
and upregulates Mitf . This inversion from NR to RPE
is rescued by exogenous FGF1/FGF2 expression (57).
Vsx2 is the earliest transcription factor in the presumptive NR, with expression initiating at E9.5 (58). While
not required for NR specification, Vsx2 is required to
maintain NR identity, in part by repressing Mitf (47, 59).
Vsx2 also plays a crucial role in RPC proliferation (discussed below). The molecular mechanisms required for
NR specification are poorly understood.
Pax6 is known to be a master regulator of eye development and its function is highly conserved. Pax6−/−
embryos fail to form eye structures (38, 60). Contact
between the mutant OV and surface ectoderm and subsequent OV invagination fails followed by OV degeneration. However, regionalization of the OV into the
456
prospective RPE and NR is sustained in Pax6−/− OV with
maintained Mitf and Vsx2 expression. Hence, Pax6 is
a critical regulator for eye development, but it is dispensable for early OV formation. PAX6 is mutated in
a number of human ocular disorders including aniridia,
coloboma, optic nerve hypoplasia and cataracts (13, 61).
Six3 is also involved in NR specification (62). NR
specification is abrogated upon the conditional loss of
Six3 in the OV. However, normal RPE development is
observed despite Six3 loss. NR arrest is attributed to
rostral expansion of Wnt8b, a transcriptional target of
SIX3 in vivo.
Development of the retina
The vertebrate retina is comprised of six neural and one
glial cell type, arising from a common pool of multipotent RPCs (63). Retinal cells are born in a temporally,
highly conserved, overlapping manner in the following order: RGC, horizontal cells, cone photoreceptors,
amacrine cells, bipolar cells, rod photoreceptors, and
Müller glia (64). Cells are organized into a trilaminar
structure in the mature retina, which include the ganglion
cell layer, the inner nuclear layer and the outer nuclear
layer. Synaptic connections are made between the cells
of the retina and are organized into additional layers
known as the inner and outer plexiform layers. Several
transcription factor families maintain RPC multipotency,
specify retinal cell fate and promote differentiation of
retina cells (Table 3).
Retinal progenitor cells
Multipotent RPC are competent to produce all seven retinal cell types. Pax6 is indispensible for maintaining RPC
multipotency. Pax6−/− RPCs produce only amacrine cells
and fail to upregulate proneural genes required to specify
the remaining retinal cell types, severely restricting RPC
competence (65).
Vsx2 plays a critical role in RPC proliferation (66). In
the ocular retardation mouse, a mutation introducing a
premature stop codon in Vsx2 impairs VSX2 production.
Eyes lacking VSX2 are significantly smaller owing to
dramatically decreased cell proliferation.
Retinal ganglion cells
RGC convey visual information from the retina to the
brain via the optic nerves composed of bundled RGC
axons. Photoreceptors process light to neurochemical
signals which are then sent to bipolar cells and finally to
RGCs and the brain. RGC are the earliest born retina cell
type. The bHLH transcription factor, Atoh7 (formerly
Math5) is required for RGC specification (67, 68). Mice
lacking Atoh7 do not produce RGCs or optic nerves.
The POU (Pit1, Oct1/Oct2, Unc-86)-homeodomain transcription factor Brn3b is required for terminal RGC
differentiation (69, 70). Brn3b expression is absent in
Atoh7 mutants, demonstrating the requirement of Atoh7
to specify RGCs and upregulate genes required for
RGC differentiation and survival (67, 68). Consequently,
Review of eye development
Table 3. Transcription factors required for specification and
differentiation of vertebrate retina cells
Retina cell type
Transcription factors expressed
Retinal progenitor
Retinal ganglion cell
Horizontal cell
Cone photoreceptor
Amacrine cell
Rod photoreceptor
Bipolar cell
Müller glia
Vsx2, Pax6,
Atoh7, Brn3b, Dlx1/Dlx2
Foxn4, Ptf1a, Onecut1
Otx2, Crx, Rorβ, Trβ2, Blimp1
Foxn4, Ptf1a, Math3, NeuroD
Otx2, Crx, Nrl, Blimp1
Vsx2, Mash1, Math3
Notch1, Hes1, Hes5, Sox2, Sox8, Sox9
Brn3b mutations result in up to 80% loss of RGC due
to increased apoptosis while RGC specification is not
affected (69, 70).
The Dlx homeobox genes also play a role in vertebrate RGC development. RGC numbers are reduced by
∼33% in the Dlx1/Dlx2 double knockout retina due to
increased apoptosis of late-born RGC (71). Dlx-mediated
RGC survival may be partly due to regulation of the
neurotrophin receptor TrkB, a downstream target upregulated by DLX2 during retinal development in vivo (72).
In addition, DLX2 positively regulates expression of
Brn3b (Zhang et al., submitted).
Horizontal cells
Horizontal cells mediate lateral interactions between
photoreceptors and bipolar cells in the outer plexiform
layer. The forkhead/winged helix transcription factor,
Foxn4, is essential for horizontal cell development (73).
Complete loss of horizontal cells and near complete
loss of amacrine cells (discussed below) occur in the
absence of Foxn4 in RPC. Downstream of Foxn4, Onecut1 and Ptf1a are required concurrently to specify horizontal cells from Foxn4+ RPCs. Similar to Foxn4 null
retinas, Ptf1a−/− retinas are devoid of horizontal and
most amacrine cells (74). Onecut1 mutants lack 80% of
horizontal cells (75). RPCs expressing only Ptf1a produce amacrine cells. Homeobox genes Prox1 and Lhx1
(Lim1), downstream of Onecut1 and Ptf1a, are critical
for horizontal cell development and laminar positioning,
respectively (76, 77).
Photoreceptors
Photoreceptors detect and convert light into visual signals by phototransduction. In addition to specifying the
forebrain and the RPE, Otx2 is also required to specify
rod and cone photoreceptors (78). Otx2 mutants specify
amacrine cells instead of photoreceptors and bipolar
cells (78). The cell fate decision for Otx2+ precursors
to become photoreceptors over bipolar cells depends on
Blimp1 (79–81). Blimp1 negatively regulates bipolar
cell specification in Otx2+ precursors by restricting Vsx2
expression required for bipolar cell development (66,
79–81). The importance for OTX2 function in retinal
development is signified by many ocular abnormalities including microphthalmia and anophthalmia (82,
83). The related Otx family member, Crx, is required
for development and maintenance of photoreceptors.
In Crx knockouts, photoreceptor outer segments fail
to develop (84). Mutations in CRX lead to human
cone-rod dystrophies and retinitis pigmentosa (85, 86).
Once photoreceptors are specified, rod or cone cell fate
depends on the expression of additional transcription
factors. Becoming a rod relies on expression of Nrl
(87). Without Nrl, prospective rods switch cell fate to
become S cones. Human NRL mutation has been linked
to retinitis pigmentosa (88). Specification of cones is
not as well described. However, it is hypothesized that
following photoreceptor commitment by Otx2, Crx and
Rorβ maintain a default S cone state, whereas expression
of Nrl drives rod development and Trβ2 expression
promotes M cone development over the default S cone
fate (87, 89, 90).
Amacrine cells
Amacrine cells, primarily located in the inner nuclear
layer, extend their processes into the inner plexiform
layer to meditate lateral interactions between bipolar
cells and RGC. Specification of amacrine cells requires
many of the same genes as horizontal cells. Foxn4
expression confers RPC competency to specify amacrine
cells, and Ptf1a, downstream of Foxn4, then determines
amacrine cell fate (73, 74). The combined loss of two
bHLH genes, Math3 and NeuroD, completely abolishes
amacrine cell production with those cells switching to
RGC and Müller glia fates (91). In the absence of Foxn4,
Math3/NeuroD expression is reduced but not abolished,
and is maintained in Ptf1a mutant retinas. Collectively,
these findings suggest a gene regulatory network where
parallel expression of Ptf1a and Math3/NeuroD drives
amacrine cell production in Foxn4+ RPC, while a distinct
RPC Foxn4- population also require Math3/NeuroD to
determine a subpopulation of amacrine cells. Many
amacrine cell subtypes exist (40+ ); this topic is beyond
the scope of this review (92).
Bipolar cells
Bipolar cells link photoreceptors and RGCs. In addition,
bipolar cells interact laterally with both amacrine cells
and horizontal cells during this process. Independent of
its role in RPC proliferation, Vsx2 is critical for bipolar
cell specification as Vsx2 null retinas have few bipolar
cells (66). As described above, Blimp1 restricts Otx2+
precursors from producing bipolar cells in favour of photoreceptors by restricting Vsx2 expression (79–81). Vsx2
restricts photoreceptor gene expression to favour bipolar cell development (93, 94). Retinas lacking expression
of both Math3 and Mash1 lose all bipolar cells with a
cell fate switch to Müller glia. Similar to amacrine cells,
bipolar cells have many subtypes defined by unique gene
expression profiles (95).
Müller glia
Müller glia cells, the last cell type produced in the developing NR, have cell processes that span the entire retina
457
Zagozewski et al.
and support retinal function. The Notch-Hes pathway is
implicated in Müller glia development. Loss of function
of Notch1, Hes1 or Hes5 reduces Müller glia cell numbers, whereas gain of function of Notch1, Hes1 or Hes5
promotes Müller glia (96, 97). The SRY-related HMG
box transcription factors Sox2, Sox8 and Sox9 are also
involved. Down-regulation of these genes also impairs
Müller glia development (98, 99). Knockdown of the Sox
transcription factors and the Notch-Hes genes promote
rod photoreceptor at the expense of Müller glia development, showing a requirement for these genes to promote
Müller glial fate over rod photoreceptors (99, 100).
Conclusions
Development of the vertebrate eye requires a complex
interplay between extracellular signalling molecules and
intrinsic transcription factors. The essential nature of
these factors is shown in the human ocular disorders
that result from their mutation. Understanding the role of
these genetic interactions in vertebrate eye morphogenesis is essential to develop novel therapies for inherited
human eye diseases.
Acknowledgements
J. L. Z. received graduate student funding from the Manitoba Health
Research Council (MHRC), from the Manitoba Institute of Child
Health (MICH) and CancerCare Manitoba Foundation (CCMF),
from the Women and Children’s Health Research Institute (WCHRI)
and the University of Alberta; Q. Z. received MHRC, MICH and
CCMF graduate student scholarships. D. D. E. has received funding
from the CIHR, The Foundation Fighting Blindness (Canada) and
the Muriel & Ada Hole Kids with Cancer Society Chair in Pediatric
Oncology (University of Alberta) in support of his retina research
programmes.
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