Transcript slides - Smith Lab

Embryogenesis
of the
human eye
8-wk
Bharesh Chauhan, PhD
Research Assistant Professor
Dept. of Ophthalmology, UPSOM
Examples of inborn errors in human eye development
Aniridia
(Dr. K. Ramaesh, FRCS FRCOphth
University of Edinburgh)
Anophthalmia
Coloboma
(Dr. W.C. Caccamise, Sr, MD
Pittsford, NY)
(Dr. B.P. Brooks, MD PhD
NEI, MD)
Stages in animal development
Gametogenesis
sperm (spermatogenesis) and ovum (oogenesis) form.
Fertilization
fusion of a sperm and ovum to generate a zygote.
Cleavage
to form morula (solid ball of blastomeres) and then
blastula (ball of cells surrounding blastocoele).
Gastrulation
Organogenesis
Growth
reorganization of blastocyst into a gastrula, consisting of endoderm,
mesoderm and ectoderm.
organ formation from the trilaminar gastrula through the processes of
patterning, differentiation, morphogenesis and growth.
correct size and shape of organs are determined by growth in
creating the fetus.
Organogenesis – the process
Regional specification
cell differentiation
morphogenesis
growth
Mammalian eye development
Optic stalk
The genetic and molecular basis of congenital eye defects.
Graw J.
Nat Rev Genet. 2003 Nov;4(11):876-88.
Photoreceptor
neurons
Developing
brain
Kismet/CHD7 regulates axon morphology, memory and locomotion
in a Drosophila model of CHARGE syndrome.
Melicharek DJ, Ramirez LC, Singh S, Thompson R, Marenda DR.
Hum Mol Genet. 2010 Nov 1;19(21):4253-64.
Origin of ocular tissues
Surface ectoderm
Neuroectoderm
Mesoderm
Neural crest
Lacrimal gland
Lens
Conjunctiva
Eyelid
Neuroretina
RPE
Ciliary and iris epithelium
Iris muscle
Optic nerve
Vitreous
Extraocular muscles
Vascular endothelium
Schlemm's canal
Blood
Temporal sclera
Corneal stroma
Corneal endothelium
Trabecular meshwork
Ciliary body and iris stroma
Choroidal stroma
Sclera
Neurulation and head patterning
• Prior to retinal development, the
following occurs during the first 3
weeks of embryogenesis:
- neural induction of the
competent ectoderm
- anterior-posterior subdivision of
the resulting neural plate.
Neural plate patterning: upstream and downstream
of the isthmic organizer.
Wurst W, Bally-Cuif L.
Nat Rev Neurosci. 2001 Feb;2(2):99-108.
Neural crest specification: migrating into genomics.
Gammill LS, Bronner-Fraser M.
Nat Rev Neurosci. 2003 Oct;4(10):795-805.
Stages in optic cup development
Placode stage
• Specification of the eye field in the diencephalon occurs at this
stage by signaling between the closely-apposed:
- epithelia of the surface ectoderm
- the lateral diverticuli of the budding diencephalon.
Lens pit stage
• The first morphological sign of eye development in vertebrates is the bilateral
evagination of the diencephalon to form the optic vesicles.
• Continued evagination leads to the formation of the optic pits with elongation
of the optic stalk driving the back of the eye further.
• Mesenchyme between the optic vesicle and the surface ectoderm is
displaced as the two tissues come into close physical contact.
Optic cup stage
• The continued evagination of the optic vesicle leads to the formation
of the optic cup, which is bilayered.
• The upper layers differentiate to form the neural retinas and the lower
layers differentiate to form the retinal pigment epithelium (RPE).
Differentiation of RPCs into retinal cell types
Intrinsically different
retinal progenitor cells
produce specific types of
progeny.
Cepko C.
Nat Rev Neurosci. 2014
Sep;15(9):615-27.
• human neural retina of the optic cup inner layer differentiates within first month
• ganglion cells start first (7-8 wks) and centrally, while bipolar and horizontal cells
start peripherally and migrate centrally,
• primitive fovea is formed from the thinning of the GCL and INL at 24-26 wks .
Optic stalk (OS) – choroidal fissure closure
• occurs at 6 weeks,
• molecular mechanism has been partially deciphered (eg., FGF, RA).
Optic nerve development
Four phases of development
1.
2.
3.
• optic stalk extension
• choroidal fissure closure (coloboma),
• migration of the RGC axons into the optic stalk towards the LGN,
• reduction of axons by apoptosis (megalopapilla)
• Myelination of the axons occurs later in gestation, 32 wks in humans
Hyaloid vasculature development
Three stage process
• deposition of hyaloid cells around
lens area and generation of a loop,
• branched networks form,
• vessel refinement occurs.
In vivo analysis of hyaloid vasculature morphogenesis in
zebrafish: A role for the lens in maturation and
maintenance of the hyaloid.
Hartsock A, Lee C, Arnold V, Gross JM.
Dev Biol. 2014 Aug 13. pii: S0012-1606(14)00376-5.
Four stages of morphogenesis in lens
development
placode
pit
vesicle
fiber
a critical phase for co-ordinated morphogenesis between
two epithelia, the optic vesicle and presumptive lens
Mechanism of invagination
Balanced Rac1 and RhoA activities
regulate cell shape and drive invagination
morphogenesis in epithelia.
Chauhan BK, Lou M, Zheng Y, Lang RA.
Proc Natl Acad Sci U S A. 2011 Nov
8;108(45):18289-94.
RhoA
Rac1
• RhoA promotes apical constriction
• Rac1 promotes cell lengthening
Inter-epithelial processes during lens placode invagination
Mann I. (1950) The Development of the
Human Eye. 2nd Ed. Grune & Stratton,
Inc. New York.
Lens pit filopodia contain active myosin II
Cdc42- and IRSp53-dependent contractile filopodia
tether presumptive lens and retina to coordinate
epithelial invagination.
Chauhan BK, Disanza A, Choi SY, Faber SC, Lou M,
Beggs HE, Scita G, Zheng Y, Lang RA.
Development. 2009 Nov;136(21):3657-67.
Does the developing lens shape the optic cup?
• Shape of the
1)
cultured optic cup
is different from
the naturally
developing optic
cup next to the
lens.
Self-organizing optic-cup morphogenesis in three-dimensional culture.
Eiraku M, Takata N, Ishibashi H, Kawada M, Sakakura E, Okuda S, Sekiguchi K, Adachi T,
Sasai Y.
Nature. 2011 Apr 7;472(7341):51-6.
2)
• Uncoupled
developing lens
and optic cups do
not conform to
canonical shape
forms.
Cdc42- and IRSp53-dependent contractile filopodia tether presumptive lens and retina
to coordinate epithelial invagination.
Chauhan BK, Disanza A, Choi SY, Faber SC, Lou M, Beggs HE, Scita G, Zheng Y,
Lang RA.
Development. 2009 Nov;136(21):3657-67.
Maturation of the lens and sutures
• Fiber cell differentiation
begins during early vesicle
stage to form primary
fibers in the posterior lens,
• lens continues enlarging
by proliferation and
elongation of the lens
equator epithelial cells to
form secondary fibers,
• The fibers adopt a
https://mutagenetix.utsouthwestern.edu/phenotypic/phenotypic_rec.cfm?pk=309
Understanding the role of growth factors in embryonic development: insights
from the lens.Lovicu FJ, McAvoy JW, de Iongh RU. Philos Trans R Soc Lond B
Biol Sci. 2011 Apr 27;366(1568):1204-18. doi: 10.1098/rstb.2010.0339. Review.
Three-dimensional organization of primary lens fiber cells. Shestopalov VI,
Bassnett S. Invest Ophthalmol Vis Sci. 2000 Mar;41(3):859-63.
hexagonal shape, a ballsocket mid-arrangement
and are bound to the lens
capsule by a foot
processes
Corneal development
Neuroblastoma book edited by Hiroyuki Shimada, ISBN 978-953-51-1128-3, Published: May 29, 2013
Chapter 4 Neurotrophin and Neurotrophin Receptor Involvement in Human Neuroblastoma
Pierdomenico Ruggeri, Antonietta R. Farina, Lucia Cappabianca, Natalia Di Ianni, Marzia Ragone,
Stefania Merolle, Alberto Gulino and Andrew R. Mackay
Angle development
The next step: detailed assessment of an
adult glaucoma patient.
Philippin H, Shah P, Burton M.
Community Eye Health. 2012;25(7980):50-3.
Origin of ocular tissues
Surface ectoderm
Neuroectoderm
Mesoderm
Neural crest
Lacrimal gland
Lens
Conjunctiva
Eyelid
Neuroretina
RPE
Ciliary and iris epithelium
Iris muscle
Optic nerve
Vitreous
Extraocular muscles
Vascular endothelium
Schlemm's canal
Blood
Temporal sclera
Corneal stroma
Corneal endothelium
Trabecular meshwork
Ciliary body and iris stroma
Choroidal stroma
Sclera