EyeDevelopment2_2023_24 - Tagged.pdf

Eye Development 2/2 Development of the lens Development of the retina and optic nerve Postnatal development of the eye http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm Anomalies of early development One or both eyes may fail to develop: Anophthalmos - Complete absence of eye (very r...

Eye Development 2/2 Development of the lens Development of the retina and optic nerve Postnatal development of the eye http://www.med.unc.edu/embryo_images/unit-eye/eye_htms/eyetoc.htm Anomalies of early development One or both eyes may fail to develop: Anophthalmos - Complete absence of eye (very rare); optic vesicle forms but then atrophies Failures of early development Microphthalmos: - small eye(s) probably due to failure of optic cup expansion & correct development of retina & vitreous - - multiple causes including: chromosome abnormalities (trisomy 13), infections during pregnancy (rubella), foetal alcohol syndrome Development of the Lens Inductive events in formation of crystalline lens Unknown diffusable induction factor Induction by diffusable factor Differentiation Oxt-2 Diffusion ? Cell from developing neural plate Cell from late gastrula stage Transcription factors: Oxt-2: eye specific gene BMP: essential for surface ectoderm to differentiate into lens placode and then for lens epithelial cells to differentiate into lens fibres Pax6: essential gene for formation of the lens and retina Sox2: essential gene for crystallin expression Differentiation Surface ectoderm Oxt-2 Pax6 Lens placode then lens vesicle Oxt-2 Pax6 Sox2 BMP Developing optic vesicle Initiation of lens fibre formation Summary of lens formation 27D 4.5wk 29D 5wk Surface ectoderm 32D 5.5wk 36D 6wk Optic stalk Neural ectoderm Separation of the lens vesicle from the surface ectoderm Lens vesicle Surface ectoderm  Section through the developing eye as the lens vesicle separates from surface ectoderm  Presence of the retina induces elongation of primary fibres from the posterior wall of the lens vesicle Primary fibres Human embryo (day 33 gestation). Carnegie embryo collection Smelser, G.K., Investigative Ophthalmology 1965, 4, 398. Formation of the lens: primary lens fibres Weeks 5 + 6 End of week 7 Copyright 1998, 1999 Leos Kral.  The newly pinched-off lens is a hollow structure surrounded by the developing lens capsule.  Under the influence of the retina, cells at the back of the lens elongate, forming primary fibres, which lose their nuclei and fill the lens by the end of week 7. Section through the early embryonic lens Fibre Hyaloid vessels Human embryo (45 days gestation, Carnegie embryo collection). Smelser, G.K., Investigative Ophthalmology 1965, 4, 398.  Lens filled with primary fibres. Note line of fibre cell nuclei.  Hyaloid vascular net encloses the developing lens.  Hyaloid vessels regress from week 11 – the adult human lens is avascular Formation of the lens: secondary lens fibres Week 8 Copyright 1998, 1999 Leos Kral.   Secondary fibres are derived from anterior cells at the equator of the lens. These cells elongate and surround the primary fibres, forming a complete ring. Primary fibres form the embryonic lens nucleus, secondary fibres - the foetal or adult nucleus and outer cortex. Formation of the lens: developed lens Copyright 1998, 1999 Leos Kral.   The majority of lens growth occurs during the foetal period, however the lens will continue to grow throughout life. Density of secondary fibres increases, with some compression of the primary nucleus. Secondary fibres form sutures. Developing lens: loss of organelles (endoplasmic reticulum, mitochondria and nuclei) in mature lens fibres Epithelium Organelle-free zone Bassnett 2002 Exp Eye Res 74:1-6 The lens continues to grow throughout life 4 month old lens 60 year old lens New-born: 6.5 mm Adult: 10 → 15 mm Presbyopia: A Surgical Textbook Amar Agarwal, MS, FRCS, FRCOphth With age tryptophan residues in crystallins become more and more oxidized which results in the yellowing of the lens. Excessive oxidation can cause aggregation of crystallins resulting in loss of transparency to visible light → cataract Development of the Retina Embryologically the retina is part of the brain   The retina develops from a hollow pouch of the neural tube (the optic vesicle), which becomes indented to form a stalked cup (the optic cup). This double-walled cup forms the retina: http://webvision.med.utah.edu/anatomy.html Developing eye at 7 weeks:  As the optic cup closes (6 weeks) the layers of the retina begin to differentiate. Pigmented retina Intraretinal space Lens Neural retina http://www.med.unc.edu/embryo_images/ Formation of the retinal pigmented epithelium  The retinal pigment epithelium (RPE) is formed from the outer, thinner layer of optic cup.  For the RPE to form correctly, the neural layer of the developing retina must be present.  The RPE is the first retinal layer to differentiate.  Melanin pigment develops in the RPE at 4-5 weeks. This is the earliest pigmentation anywhere in the embryo. RPE Adult Macula Milam, AH and John, Sinoj K: http://www.eyepathologist.com/ Pigment-generating cells: melanocytes and specialised epithelial cells  Melanocytes are derived from the neural crest (including melanocytes in the choroid and in the stroma of the iris and ciliary body, skin and hair follicle).  In the eye, pigmented cells can also be derived from the neuroectoderm (the optic cup): retinal, iris and ciliary pigment epithelial cells.  In an individual with genetic defect in melanin synthesis (albinism) either one or both types of melanin-producing cells may be affected. Oculocutaneous albinism: both skin (including hair) and eyes are affected In ocular albinism, only the eyes are affected. Eye colour can vary greatly.    Ocular albinism: importance of the RPE Oculocutaneous albinism Ocular albinism underdeveloped macula resulting in foveal hypoplasia Ocular Albinism: Importance of the RPE Inductive signals derived from melanin synthesis in the RPE are necessary for normal development of the sensory retina. Their absence can lead to a number of retinal abnormalities:        Absence of pigmentation in RPE Underdeveloped macula, no macular pigment Fovea may be absent, lack of foveal pit Number of rods is decreased Abnormal projections of RGCs axons to the lateral geniculate nucleus Poor visual acuity, photophobia, nystagmus Melanin http://www1.imperial.ac.uk/medicine/about/divisions/nhli/molecular/membrane_traffic/ Ocular albinism: abnormal projections of retinal ganglion cell axons to the lateral geniculate nucleus The anterior part of the optic cup forms the inner layer of the iris and contributes to the formation of the ciliary body Rim of optic cup Anterior 1/5th of the optic cup Oyster, CW The human eye: structure and function CMZ – ciliary marginal zone – source o retinal stem and progenitor cells in larval frogs, fish, and birds but not in adult mammals The posterior part of the neural layer thickens with dividing progenitor cells The posterior 4/5 of the neural layer is the photoreceptive layer and contains undifferentiated progenitor cells capable of forming any of the cell types found in the sensory retina. Oyster, CW The human eye: structure and function Formation of the retina at 1.5 months RPE Proliferating zone Marginal zone The intraretinal space separating the RPE from neural retina is lost during week 7. As the choroidal fissure closes (~ week 6-7) proliferating cells in the inner layer of the optic cup migrate to form two layers: - the proliferative or germinative zone and - the anuclear marginal zone. A thin lamina (basement membrane of the inner layer of the optic cup) separates the marginal zone from the vitreal cavity. This is the precursor to the internal limiting membrane. Basement membrane of optic cup Vitreous Pediatric Retina edited by Mary Elizabeth Hartnett Formation of the retina: 2.5 months  Cells migrate to form inner and outer neuroblastic layers, separated by the anuclear transient layer of Chievitz. Formation of the 2 neuroblastic layers completes during 3rd month of gestation. RPE Outer neuroblastic layer Inner neuroblastic layer Progenitor cells will form rod & cone cells (which remain in the outer neuroblastic layer) and bipolar and horizontal cells (which migrate to the inner neuroblastic layer). Transient Layer of Chievitz (anuclear) separates layers in primitive retina, but is later obliterated by cell migration from outer neuroblastic layer. Progenitor cells will form ganglion, amacrine and Műller cells. Nerve fibres N.B: ‘-blast’ means an undifferentiated or immature cell 4.5 months: retinal lamination is essentially complete RPE Photoreceptors Outer plexiform layer Inner nuclear layer Inner plexiform layer Ganglion cell layer Nerve fibres ONL: large cone nuclei are aligned adjacent to the RPE. Photoreceptor outer segments not yet formed. OPL has established primitive lamellar synapses between bipolar cell dendrites and cone pedicles. INL is differentiating. IPL (fibres of bipolar, ganglion and amacrine cells supported by Műller fibres) has started to establish sites of primitive synapses. Ganglion cells are multilayered. Formation of the retina: 5.5 months RPE Outer segments Outer nuclear layer Outer plexiform layer Inner nuclear layer Inner plexiform layer Ganglion cell layer Nerve fibres Growing photoreceptor outer segments project between RPE and external limiting membrane. ONL consists of 6-7 layers of nuclei, outermost layers are cones aligned to external limiting membrane. OPL has a linear arrangement of synapses between bipolar cells & rod spherules. Cells in INL differentiate to form Műller cell nuclei and amacrine cells (both from the inner neuroblastic layer). INL also contains bipolar & horizontal cells (originally from the outer neuroblastic layer). Ganglion cells thinned out to one or two layers (except macula). Formation of the sensory retina  Retina has a centre to periphery developmental gradient: starts from the site of the future fovea and extends outward  Differentiation begins at about week 9 with formation of the ganglion cells, then horizontal cells and cones.  By week 10 the first amacrine cells, rods, Műller’s cells and bipolar cells form.  The same waves of cell development are apparent in the periphery, but begin later.  The last rods, Műller’s cells and bipolar cells in human retina are formed postnatally.  Synapse formation follows same plan, occurring first in the fovea, a week or so after the first cells in a given region are born, then spreading outwards to the periphery. Summary of the neural retina formation: Nerve fibre layer Marginal zone Inner neuroblastic layer Proliferating zone Transient layer of Chievitz Outer neuroblastic layer Ganglion Ganglion cell layer Amacrine Inner plexiform layer Muller Inner nuclear layer Bipolar Horizontal Photoreceptor From: Remington, LA Clinical Anatomy of the visual system Outer plexiform layer Outer nuclear layer Inner segment layer Outer segment layer Synaptogenesis in the peripheral retina  Formation of synapses between the major neuronal classes of the retina occurs in three major phases:  Retinal ganglion cells and amacrine cells form the earliest functional circuits of the inner plexiform layer (IPL).  Later, horizontal cells and photoreceptors form contacts in the outer retina, giving rise to the outer plexiform layer (OPL).  Vertical networks in the inner and outer retina are later interconnected when bipolar cells form connections with ganglion cells. http://webvision.med.utah.edu/Wong.html Formation of the fovea   The fovea is the first part of the retina to develop but the last to mature. The future fovea starts to form at approximately 22 weeks, initially as a thickened layer of ganglion cell nuclei, which will give way to the foveal pit. Fovea John Moran Eye Center, University of Utah  Foveal pit forms by cell migration First the ganglion then inner nuclear layer cells migrate away from the centre of the future fovea. 40 week foetus adult Provis, J. M. et al. Arch Ophthalmol 2008;126:507-511.  Later, cones (particularly L-and Mcones) migrate into the fovea, increasing the central cone density.  Much of the fovea development occurs postnatally. Retinal cell density is determined by expansion, migration and apoptosis Retina  Foveal cell density is mostly a result of migration and (lack of) expansion.  Peripheral cell density is due to a combination of migration away from the fovea, greater retinal expansion and apoptosis of ganglion cells. GC layer Fovea Bipolar cell layer  Photoreceptors Changes in cell density due to retinal expansion and migration continue for some years. At birth cone cells are immature  Inner segments are thick and outer segments short  Cone inner segment achieves adult length at ~36 months Cone outer segment matures ~6 years   Mature cones are thinner in the centre of the fovea than elsewhere in the retina allowing more to be packed into a small area (→ better visual acuity) Large blood vessels in the retina formed by vasculogenesis  Vasculogenesis: formation of new vessels from precursor cells  Vascular precursor cells appear near the optic nerve head following the first phase of differentiation in the central retina  Vasculogenesis spreads through the nerve fibre layer from the optic nerve head to the periphery, avoiding the fovea Central retinal artery and capillary beds form by angiogenesis  Central retinal artery supplies the inner neural retina, dividing to form arterioles which run through the different layers of the neural retina forming a capillary network.  Central retinal artery and vein are derived by angiogenesis (budding) from regressing hyaloid vessels.  Capillary beds initially form around the optic nerve head (when large surface vessels have almost reached the ora serrata).  Capillaries ramify at several levels in the retina. Shallow capillary beds lie on either side of the GC layer, deep capillaries on either side of the INL. Dr. Gordon K. Klintworth, http://www.eyepathologist.com/ Retinopathy of prematurity  photoreceptors  inl ipl Inner nuclear layer GC  Ganglion cells Blood vessels Normal adult http://www.eyepathologist.com Newborn  When in the incubator under increased O2: immature retinal blood vessels respond to high O2 levels by vasoconstriction and cease development. After removal of supplemental O2: rebound vascular proliferation occurs, but new vessels poorly formed and ‘leaky’. New vessels may grow into vitreous or form vitreoretinal adhesions. Fundus appearance monitored to regulate O2 exposure and try to reduce neovascularisation. Development of the Optic Nerve Formation of the Optic Nerve http://www.vision.ca/eye/retina_o.nerve.html  Closure of the choroidal fissure (week 6) traps the hyaloid artery creating a 2 layered optic stalk.  The outer layer forms the neuroglial sheath that surrounds the optic nerve and gives rise to glial components of the lamina cribrosa. Formation of the Optic Nerve    http://www.vision.ca/eye/retina_o.nerve.html Apoptosis of the inner layer provides a passage for developing ganglion cell axons growing to the CNS (from week 8). Other cells of the inner wall become the glial cells of the optic nerve. Growth of GC axons into the optic nerve peaks at 4 months. Numbers of GC axons decline as they are pruned by apoptosis over the next 5 to 6 weeks and adult numbers are established by birth. Section through the adult optic nerve  Myelination of axons begins at the lateral geniculate nucleus during 5th month, reaches optic chiasma at 6 months gestation and stops at the lamina cribrosa at 1-3 months after birth. Blood vessels (central retinal artery and vein) Lamina cribrosa http://www.eyepathologist.com/ Bundles of axons Postnatal development of the eye Postnatal Development  The eye of a newborn infant is approximately 70% of the length and 35% of the volume of an adult eye.  Different parts of the eye grow at different rates & reach adult size at different ages:  Axial length - 12 to 16 years old  Anterior chamber depth - 8 to 12 years old  Corneal area & thickness - approximately 3 years old  The lens continues to grow throughout life and the inner nucleus becomes very dense. The ability of the lens to change shape for accommodation declines with age → presbyopia. Postnatal Development  In newborns: cones in the fovea are immature & less dense than in adult  adult visual acuity is achieved at 5 to 7 years after birth due to the maturation of the fovea.  adult cone density is reached at the age of 5-7 years. Increased density of foveal cones is due to both migration & tighter packing of foveal cones as they mature.  Colour discrimination is relatively poor at birth, due to the immaturity of cones, but improves rapidly. At 3 months red/green can be discriminated, with blue being added later. At one year, colour vision is similar to adults.  The retina outside the fovea is relatively more mature: rod cells are mature at birth. Emmetropization Process by which the eye adjusts itself to maintain normal vision  Refractive error is variable in infants (approx 28% myopic at birth). However, at age 6 – 7 years, 90% of children have no significant refractive error.  Optical elements (corneal and lens curvature, anterior chamber depth) decrease in power with growth. The retina compensates by controlling growth of the sclera (and therefore the rate at which the eye axial length increases) to maintain focusing ability.  Retina must detect image blur and distinguish hyperopic from myopic blur to generate a signal that increases or decreases scleral growth to compensate for refractive error. Learning outcomes from Lecture 2 on eye development:         Appreciate the importance of induction in eye development, in which each new structure in turn effects the development of other structures. Understand the development of the lens from induction of the surface ectoderm (to form the lens placode), to the adult structure containing primary and secondary fibres. How does the presence of the developing retina influence the development of the lens? When does the lens cease to grow? Be able to explain the early development of the retina from the outgrowth from the neural tube (forebrain), and formation of the RPE. How do the neural retina and RPE influence each other development? Be able to explain and define ocular albinism. What are its effects? Appreciate the early formation of the retina and how the migration and differentiation of cells forms adult cell layers. Formation of synaptic networks. Appreciate development of the fovea and be aware of differences between the fovea and peripheral retina. Appreciate how the optic nerve is formed. Appreciate that development of the eye continues into childhood.