Transcript Surface ectoderm

Visual Neuroscience 6100
Early Eye Development
2/14/05
The mature vertebrate eye
http://webvision.med.utah.edu/
Human brain development
Lateral view (A) and midline extended diagram (B) of a 6-week human brain
showing secondary bulges of the neural tube. (After Langman, 1969)
• Eye field specification and separation
• Eye morphogenesis
• Anterior segment development:
Lens and ciliary body
• Vasculogenesis
• Optic vesicle patterning:
Neural retina
Retinal pigmented epithelium (RPE)
Optic stalk
Fate map of the presumptive brain areas of the Xenopus neural plate
(stage 15, left) and mouse neural plate (E7, right).
Area olfactoria primitiva 1 Primordium hipppocampi 3 Supra
chiasmatic nucleus 7 Ventr. hypothalamic nucleus 9 Anterior
thalamic nucleus 13 Praetecum 16 Optic tectum 17
Hypophysis 1Cerebellum 19 Epiphysis 20 Tegmentum
dorsale 21 Choroid plexus 23 Medulla oblongata 24
E7 = embryonic day 7
Expression of eyeless (Drosophila Pax6) in imaginal
discs induces ectopic eyes.
- induction of ectopic eyes in
structures such as legs,
antennae and wings
- eye morphogenesis is
essentially normal
- the photoreceptors were
electrically active upon
illumination
Halder et al. (1995) Science 267: 1788
Ectopic eyes induced by Pax-6 misexpression resemble
normal eyes morphologically and histologically.
Xenopus embryos were injected with
160 pg of Pax6 RNA in one animal
pole blastomere at the 16-cell stage
and fixed at stage 48.
(A-C) Ectopic eyes from different
embryos displaying eye cup (white
arrowhead) and lens (black
arrowhead). RPE-like extension
from eye cup (C, arrow).
(G-I) Hematoxylin and eosin staining
of coronal sections through (G)
normal eye, and (H,I) ectopic eyes.
Arrows indicate ciliary margin zone in
normal eye and region with similar
morphology in ectopic eyes.
Chow et al. (1999) Development 126: 4213
The pattern of Pax-6 expression over time in Xenopus embryos supports
formation of two retina primordia from a single eye field.
Li et al. (1997) Development 124: 603
How does the eye field resolve into two separate domains?
?
Hypothesis:
The underlying tissue (ventral diencephalon) provides a signal to
suppress retina formation in its median region resulting in the
resolution of the retina field into two retina primordia.
Prechordal plate suppresses Pax6 expression and resolves the eye field
into two bilateral domains.
Transplantation of an additional prechordal plate underneath the left
retinal primordium supresses Pax-6 expression in the left eye.
Removal of the prechordal plate
in chick embryos leads to
holoprosencephaly and
formation of a cyclopean eye.
Li et al. (1997) Development 124: 603
Brain and eye defects in mouse embryos lacking sonic hedgehog:
holoprosencephaly and cyclopia (synophthalmia).
Otx-2 mRNA expression:
wildtype
shh-/shh-
In the mutant animal, no midline forms, and there is a single,
continuous optic vesicle in the ventral region.
Chiang et al. (1996) Nature 383: 407
Hedgehog (shh) signaling from the ventral diencephalon
regulates separation of the eye field.
shh
Modified from Li et al. 1997
• Eye field specification and separation
• Eye morphogenesis
• Anterior segment development:
Lens and ciliary body
• Vasculogenesis
• Optic vesicle patterning:
Neural retina
Retinal pigmented epithelium (RPE)
Optic stalk
From eye field to optic vesicle (mouse).
Eye field E7
Optic sulci E8.5
Optic vesicle E9
Optic vesicle E9.5
http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm
Defects in eye morphogenesis result in microphthalmia or anophthalmia.
Anophthalmia caused by a mutation of the transcription factor RAX.
Voronina et al. (2004) Human Mol Genetics 13: 315.
Morphogenesis of the optic cup
Optic
vesicle
lens
placode
E9.5
E10
E11
E13
http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm
Morphogenesis of the retinal layers
The neural retina expands by extensive proliferation and becomes stratified.
The RPE remains a single layer of cuboidal cells and becomes pigmented (E11-E14).
http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm
Morphogenesis of the optic stalk
Otteson et al. (1998) Dev Biol 193:209.
Defects in morphogenesis of the optic stalk result in coloboma.
• Eye field specification and separation
• Eye morphogenesis
• Anterior segment development:
Lens and ciliary body
• Vasculogenesis
• Optic vesicle patterning:
Neural retina
Retinal pigmented epithelium (RPE)
Optic stalk
Formation of the ciliary body and iris separates the eye into
posterior and anterior chambers.
http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm
Defects in anterior segment development can cause congenital glaucoma
(e.g. Axenfeld-Rieger syndrome).
Developmental disorders of the ocular
anterior segment are often associated
with elevated intraocular pressure and
glaucoma. Known genes that cause
anterior segment dysgenesis code for
developmentally important
transcription factors (PITX2, PITX3,
PAX6, FOXE3).
Glaucoma can cause damage when
the aqueous humor, a fluid that
inflates the front of the eye and
circulates in a chamber called the
anterior chamber, enters the eye but
cannot drain properly from the eye.
Elevated pressure inside the eye, in
turn, can cause damage to the optic
nerve or the blood vessels in the eye
that nourish the optic nerve.
Anterior segment: cornea, iris, lens, ciliary
body, and ocular drainage structures
(trabecular meshwork and Schlemm’s canal).
http://www.nei.nih.gov/health/glaucoma/
Morphogenesis of the lens in the mouse eye.
Lens placode
E10
Lens vesicle
E11
Lens vesicle
E12.5
Lens with differentiating lens fibers around E17
http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm
Different signals control proliferation and differentiation of lens
epithelium into lens fibers.
Lovicu and McAvoy (2005): Dev Biol.
• Eye field specification and separation
• Eye morphogenesis
• Anterior segment development:
Lens and ciliary body
• Vasculogenesis
• Optic vesicle patterning:
Neural retina
Retinal pigmented epithelium (RPE)
Optic stalk
The Tunica Vasculosa Lentis and Pupillary Membrane are
transient vascular structures in the eye.
The hyaloid artery develops from
mesenchymal tissue in the embryonic fissure
(top left) and is the primary source of nutrition
in the embryonic retina. It courses from the
primitive optic nerve to the posterior lens
capsule and forms a capillary network around
the lens, the tunica vasculosa lentis. It
anastomoses anteriorly with the pupillary
membrane (bottom left), which consists of
vessels and mesenchyme overlying the
anterior lens capsule. Later during
development, the hyaloid vasculature and
pupillary membrane regress. The choroid and
radial intraretinal vessels become the main
source of blood supply and nutrition in the
eye.
Improper oxygen supply in the fetal eye can
lead to retinopathy of prematurity (ROP).
http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm
Origin of ocular and extraocular tissues.
Neural ectoderm (optic cup): neural retina, RPE, pupillary sphincter and dilator
muscles, posterior iris epithelium, optic nerve.
Neural crest (connective tissue): corneal endothelium, trabecular meshwork
stroma of cornea, iris and ciliary body, ciliary muscle, choroids and sclera,
perivascular connective tissue and smooth muscle cells, meninges of optic
nerve, orbital cartilage and bone, connective tissue of the extrinsic ocular
muscles, secondary vitreous, zonules.
Mesencephalic neural crest cells populate the region around the optic vesicle and ultimately
give rise to nearly all the connective tissue structures of the avian eye, and the same can be
presumed for the mammalian eye.
Surface ectoderm (epithelium): corneal and cojunctival epithelium, lens, lacrimal
gland, eyelid epidermis, eyelid cilia, epithelium of adnexa glands, epithelium of
nasolacrimal duct.
Mesoderm (muscle and vascular endothelium): extraocular muscles, vascular
endothelia, Schlemm’s canal endothelium, blood.
• Eye field specification and separation
• Eye morphogenesis
• Anterior segment development:
Lens and ciliary body
• Vasculogenesis
• Optic vesicle patterning:
Neural retina
Retinal pigmented epithelium (RPE)
Optic stalk
The optic vesicle is already
patterned into the
presumptive neural retina
and the presumptive RPE.
Mitf
Chx10
Fuhrmann et al (2000) Development 127: 4599
What regulates patterning of the optic vesicle?
head
mesenchyme
surface
ectoderm
RPE
RPE
dorsal
proximal
ventral
diencephalon
distal
ventral
Neural retina: Pax6, Chx10
RPE: Mitf
Optic stalk: Pax2
The eye domains are sensitive to sonic hedgehog.
Injection of shh leads to formation of
reduced optic primordia.
shh has opposite effects on Pax-2 and
Pax-6 expression in the optic primordia:
it reduces Pax-6 expression (A-C) and
induces ectopic Pax-2 expression (D-F).
Macdonald et al. (1995) Development 121: 3267
Sonic hedgehog from the ventral diencephalon
promotes optic stalk formation.
head
mesenchyme
surface
ectoderm
RPE
RPE
dorsal
proximal
ventral
diencephalon
distal
ventral
Neural retina: Pax6, Chx10
RPE: Mitf
Optic stalk: Pax2
FGF in the lens (surface) ectoderm patterns the presumptive neural retina.
In the normal optic vesicle, the RPE
inducing gene Mitf is expressed first in
the whole optic vesicle and becomes
then restricted to the presumptive
RPE (right), but not after removal of
surface ectoderm (below).
Nguyen and Arnheiter (2000) Development 127: 3581
FGF is a candidate signal
expressed in the surface ectoderm
(left) that suppresses RPE
development in the distal optic
vesicle and promotes
differentiation of the retina (right).
Pittack et al. (1997) Development 124: 805
FGF from the surface ectoderm induces the
neural retina in the distal optic vesicle.
head
mesenchyme
surface
ectoderm
RPE
FGF1/2
RPE
dorsal
proximal
ventral
diencephalon
distal
ventral
Neural retina: Pax6, Chx10
RPE: Mitf
Optic stalk: Pax2
Extraocular mesenchyme (activin) induces the proximal optic vesicle to
develop into the retinal pigmented epithelium.
in vivo
explant
+ mes
explant mes
explant +
activin
Mitf
Chx10
Fuhrmann et al (2000) Development 127: 4599
E11.5
Transdifferentiation of the dorsal RPE occurs in mice
with a defect in the head mesenchyme
(targeted deletion of the transcription factor AP2).
J. West-Mays et al. 1999
An activin-like (?) signal from the head mesenchyme induces the RPE
domain in the optic vesicle.
head
mesenchyme
surface
ectoderm
RPE
FGF1/2
RPE
dorsal
proximal
ventral
diencephalon
distal
ventral
Neural retina: Pax6, Chx10
RPE: Mitf
Optic stalk: Pax2
Interference with sonic hedgehog signaling causes defects in RPE
development in the embryonic chick eye.
shh
expression
patched
expression
untreated E6
implantation
of cells producing
blocking shhantibody
Zhang and Yang (2001) Dev Biol 233: 271
Ventral RPE formation is dependent upon sonic hedgehog expressed in
the ventral diencephalon in mouse.
wildtype
BF-1 KO
BF-1 KO
Huh et al. (1999) Dev Biol 211: 53
Deletion of the gene encoding for the transcription factor Brain factor-1 results
in the loss of sonic hedgehog expression in the ventral forebrain.
Extracellular signals regulate patterning of the optic vesicle.
head
mesenchyme
surface
ectoderm
RPE
FGF1/2
RPE
dorsal
proximal
ventral
diencephalon
distal
ventral
Neural retina: Pax6, Chx10
RPE: Mitf
Optic stalk: Pax2
Hedgehog signaling from the ventral diencephalon regulates:
separation of the eye field
optic stalk formation
ventral RPE patterning
Modified from Stenkamp and Frey, 2003