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Embryogenesis of the human eye Bharesh Chauhan, PhD

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1 Embryogenesis of the human eye Bharesh Chauhan, PhD
8-wk Bharesh Chauhan, PhD Research Assistant Professor Dept. of Ophthalmology, UPSOM

2 Examples of inborn errors in human eye development
Aniridia Anophthalmia Coloboma (Dr. K. Ramaesh, FRCS FRCOphth University of Edinburgh) (Dr. W.C. Caccamise, Sr, MD Pittsford, NY) (Dr. B.P. Brooks, MD PhD NEI, MD)

3 Stages in animal development
Gametogenesis Fertilization Cleavage Gastrulation Organogenesis Growth sperm (spermatogenesis) and ovum (oogenesis) form. fusion of a sperm and ovum to generate a zygote. to form morula (solid ball of blastomeres) and then blastula (ball of cells surrounding blastocoele). 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.

4 Organogenesis – the process
Regional specification cell differentiation morphogenesis growth

5 Mammalian eye development
Optic stalk The genetic and molecular basis of congenital eye defects. Graw J. Nat Rev Genet Nov;4(11): 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 Nov 1;19(21): Photoreceptor neurons Developing brain

6 Origin of ocular tissues

7 Neurulation and head patterning
Neural plate patterning: upstream and downstream of the isthmic organizer. Wurst W, Bally-Cuif L. Nat Rev Neurosci Feb;2(2): Neural crest specification: migrating into genomics. Gammill LS, Bronner-Fraser M. Nat Rev Neurosci Oct;4(10): 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.

8 Stages in optic cup development

9 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.

10 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. Coronal section of the embryonic head

11 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).

12 Differentiation of RPCs into retinal cell types
Intrinsically different retinal progenitor cells produce specific types of progeny. Cepko C. Nat Rev Neurosci Sep;15(9): 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 wks .

13 Optic stalk (OS) – choroidal fissure closure
occurs at 6 weeks, molecular mechanism has been partially deciphered (eg., FGF, RA).

14 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

15 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 Aug 13. pii: S (14)

16 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

17 Mechanism of invagination
RhoA Rac1 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 Nov 8;108(45): • RhoA promotes apical constriction • Rac1 promotes cell lengthening

18 Inter-epithelial processes during lens placode invagination
Mann I. (1950) The Development of the Human Eye. 2nd Ed. Grune & Stratton, Inc. New York.

19 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 Nov;136(21):

20 Does the developing lens shape the optic cup?
1) 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 Apr 7;472(7341):51-6. Shape of the cultured optic cup is different from the naturally developing optic cup next to the lens. 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 Nov;136(21): 2)

21 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 hexagonal shape, a ball-socket mid-arrangement and are bound to the lens capsule by a foot processes 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 Apr 27;366(1568): doi: /rstb Review. Three-dimensional organization of primary lens fiber cells. Shestopalov VI, Bassnett S. Invest Ophthalmol Vis Sci Mar;41(3):

22 Corneal development Neuroblastoma book edited by Hiroyuki Shimada, ISBN , 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

23 Angle development The next step: detailed assessment of an adult glaucoma patient. Philippin H, Shah P, Burton M. Community Eye Health. 2012;25(79-80):50-3.

24 Origin of ocular tissues


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