Visual Neuroscience 6100 Early Eye Development 2/14/05.

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 retinaRetinal 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

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.

Ectopic eyes induced by Pax-6 misexpression resemble normal eyes morphologically and histologically.

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.

Removal of the prechordal plate in chick embryos leads to holoprosencephaly andformation of a cyclopean eye.

Transplantation of an additional prechordal plate underneath the left retinal primordium supresses Pax-6 expression in the left eye.

Li et al. (1997) Development 124: 603

Brain and eye defects in mouse embryos lacking sonic hedgehog: holoprosencephaly and cyclopia

(synophthalmia).

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

wildtype

shh-/shh-

Otx-2 mRNA expression:

Hedgehog (shh) signaling from the ventral diencephalon regulates separation of the eye field.

Modified from Li et al. 1997

shh




• Vasculogenesis


From eye field to optic vesicle (mouse).

http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm

Eye field E7 Optic sulci E8.5 Optic vesicle E9

Optic vesicle E9.5

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

lensplacode

Opticvesicle

E9.5 E10 E11 E13


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).


Morphogenesis of the optic stalk

Otteson et al. (1998) Dev Biol 193:209.

Defects in morphogenesis of the optic stalk result in coloboma.




• Vasculogenesis


Formation of the ciliary body and iris separates the eye into posterior and anterior chambers.


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.

http://www.nei.nih.gov/health/glaucoma/

Defects in anterior segment development can cause congenital glaucoma (e.g. Axenfeld-Rieger syndrome).

Anterior segment: cornea, iris, lens, ciliary body, and ocular drainage

structures (trabecular meshwork and Schlemm’s canal).



Morphogenesis of the lens in the mouse eye.

Lens with differentiating lens fibers around E17


Lens placodeE10

Lens vesicleE11

Lens vesicleE12.5

Lovicu and McAvoy (2005): Dev Biol.

Different signals control proliferation and differentiation of lens epithelium into lens fibers.




• Vasculogenesis


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).


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.

Origin of ocular and extraocular tissues.




• Vasculogenesis


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?

ventral diencephalon

surface ectoderm

headmesenchyme

proximal

ventral

distal

dorsal

SHHSHH

retinaretina

optic stalk

optic stalk

RPERPE

Neural retina: Pax6, Chx10Neural retina: Pax6, Chx10RPE: MitfRPE: MitfOptic stalk: Pax2Optic stalk: Pax2

RPERPE

Macdonald et al. (1995) Development 121: 3267

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).

Sonic hedgehog from the ventral diencephalon promotes optic stalk formation.


surface ectoderm

headmesenchyme

proximal

ventral

distal

dorsal

SHHSHH

retinaretina

optic stalk

optic stalk

RPERPE


RPERPE

Pittack et al. (1997) Development 124: 805

Nguyen and Arnheiter (2000) Development 127: 3581

FGF in the lens (surface) ectoderm patterns the presumptive neural retina.

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).

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).

FGF from the surface ectoderm induces the neural retina in the distal optic

vesicle.


surface ectoderm

headmesenchyme

proximal

ventral

distal

dorsal

FGF1/2FGF1/2

SHHSHH

retinaretina

optic stalk

optic stalk

RPERPE


RPERPE

Fuhrmann et al (2000) Development 127: 4599

Extraocular mesenchyme (activin) induces the proximal optic vesicle to develop into the retinal pigmented epithelium.

Mitf

Chx10

in vivoexplant + mes

explant - mes

explant + activin

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

E1

1.5

E1

2.5

An activin-like (?) signal from the head mesenchyme induces the RPE domain in the optic vesicle.


surface ectoderm

headmesenchyme

proximal

ventral

distal

dorsal

activinactivin

FGF1/2FGF1/2

SHHSHH

retinaretina

optic stalk

optic stalk

RPERPE


RPERPE

Interference with sonic hedgehog signaling causes defects in RPE development in the embryonic chick eye.

Zhang and Yang (2001) Dev Biol 233: 271

shh expression

patched expression

untreated E6

implantationof cells producing

blocking shh-antibody

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: 53Deletion 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.


surface ectoderm

headmesenchyme

proximal

ventral

distal

dorsal

activinactivin

FGF1/2FGF1/2

SHHSHH

retinaretina

optic stalk

optic stalk

RPERPE


RPERPE

Hedgehog signaling from the ventral diencephalon regulates:

separation of the eye field

optic stalk formation

ventral RPE patterning

Modified from Stenkamp and Frey, 2003

Visual Neuroscience 6100 Early Eye Development 2/14/05.

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Transcript of Visual Neuroscience 6100 Early Eye Development 2/14/05.