Talk:Sensory - Vision Development

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Cite this page: Hill, M.A. (2021, September 18) Embryology Sensory - Vision Development. Retrieved from


The relationship between eye movement and vision develops before birth

Front Hum Neurosci. 2014 Oct 2;8:775. doi: 10.3389/fnhum.2014.00775. eCollection 2014.

Schöpf V1, Schlegl T2, Jakab A2, Kasprian G1, Woitek R1, Prayer D1, Langs G3.


While the visuomotor system is known to develop rapidly after birth, studies have observed spontaneous activity in vertebrates in visually excitable cortical areas already before extrinsic stimuli are present. Resting state networks and fetal eye movements were observed independently in utero, but no functional brain activity coupled with visual stimuli could be detected using fetal fMRI. This study closes this gap and links in utero eye movement with corresponding functional networks. BOLD resting-state fMRI data were acquired from seven singleton fetuses between gestational weeks 30-36 with normal brain development. During the scan time, fetal eye movements were detected and tracked in the functional MRI data. We show that already in utero spontaneous fetal eye movements are linked to simultaneous networks in visual- and frontal cerebral areas. In our small but in terms of gestational age homogenous sample, evidence across the population suggests that the preparation of the human visuomotor system links visual and motor areas already prior to birth. KEYWORDS: ICA; development; eye movement; functional connectivity; in utero fMRI

PMID 25324764


The homeobox gene Otx2 in development and disease

Exp Eye Res. 2013 Jun;111:9-16. doi: 10.1016/j.exer.2013.03.007. Epub 2013 Mar 21.

Beby F1, Lamonerie T.


The Otx2 gene encodes a transcription factor essential for the normal development of brain, cerebellum, pineal gland, and eye. In the retina, Otx2 has essential functions from early embryogenesis to adulthood. As soon as the optic vesicle is formed, the gene is required for retinal pigment epithelium specification. Otx2 is also a key regulator of photoreceptor genesis and differentiation, and is required after birth for bipolar cells terminal maturation. Otx2 expression is maintained in the differentiated retina wherein the gene is critical for the outer retina maintenance. In the visual cortex, the gene modulates the neuronal plasticity through a paracrine mechanism. OTX2 heterozygous mutations in humans have been linked to severe ocular malformations associated with brain abnormalities and pituitary dysfunction. Recent studies have also established the OTX2 gene as an oncogene for medulloblastoma, a malignant brain tumour originating in the cerebellum. Copyright © 2013 Elsevier Ltd. All rights reserved.

PMID 23523800


A Regulatory Loop Involving PAX6, MITF, and WNT Signaling Controls Retinal Pigment Epithelium Development

PLoS Genet. 2012 Jul;8(7):e1002757. Epub 2012 Jul 5.

Bharti K, Gasper M, Ou J, Brucato M, Clore-Gronenborn K, Pickel J, Arnheiter H. Source Mammalian Development Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, United States of America.


The separation of the optic neuroepithelium into future retina and retinal pigment epithelium (RPE) is a critical event in early eye development in vertebrates. Here we show in mice that the transcription factor PAX6, well-known for its retina-promoting activity, also plays a crucial role in early pigment epithelium development. This role is seen, however, only in a background genetically sensitized by mutations in the pigment cell transcription factor MITF. In fact, a reduction in Pax6 gene dose exacerbates the RPE-to-retina transdifferentiation seen in embryos homozygous for an Mitf null allele, and it induces such a transdifferentiation in embryos that are either heterozygous for the Mitf null allele or homozygous for an RPE-specific hypomorphic Mitf allele generated by targeted mutation. Conversely, an increase in Pax6 gene dose interferes with transdifferentiation even in homozygous Mitf null embryos. Gene expression analyses show that, together with MITF or its paralog TFEC, PAX6 suppresses the expression of Fgf15 and Dkk3. Explant culture experiments indicate that a combination of FGF and DKK3 promote retina formation by inhibiting canonical WNT signaling and stimulating the expression of retinogenic genes, including Six6 and Vsx2. Our results demonstrate that in conjunction with Mitf/Tfec Pax6 acts as an anti-retinogenic factor, whereas in conjunction with retinogenic genes it acts as a pro-retinogenic factor. The results suggest that careful manipulation of the Pax6 regulatory circuit may facilitate the generation of retinal and pigment epithelium cells from embryonic or induced pluripotent stem cells.

PMID 22792072

Activation of c-Jun N-Terminal Kinase (JNK) during Mitosis in Retinal Progenitor Cells

PLoS One. 2012;7(3):e34483. Epub 2012 Apr 4.

Ribas VT, Gonçalves BS, Linden R, Chiarini LB. Source Instituto de Biofísica Carlos Chagas Filho, UFRJ, Rio de Janeiro, Brasil.


Most studies of c-Jun N-terminal Kinase (JNK) activation in retinal tissue were done in the context of neurodegeneration. In this study, we investigated the behavior of JNK during mitosis of progenitor cells in the retina of newborn rats. Retinal explants from newborn rats were kept in vitro for 3 hours and under distinct treatments. Sections of retinal explants or freshly fixed retinal tissue were used to detect JNK phosphorylation by immunohistochemistry, and were examined through both fluorescence and confocal microscopy. Mitotic cells were identified by chromatin morphology, histone-H3 phosphorylation, and location in the retinal tissue. The subcellular localization of proteins was analyzed by double staining with both a DNA marker and an antibody to each protein. Phosphorylation of JNK was also examined by western blot. The results showed that in the retina of newborn rats (P1), JNK is phosphorylated during mitosis of progenitor cells, mainly during the early stages of mitosis. JNK1 and/or JNK2 were preferentially phosphorylated in mitotic cells. Inhibition of JNK induced cell cycle arrest, specifically in mitosis. Treatment with the JNK inhibitor decreased the number of cells in anaphase, but did not alter the number of cells in either prophase/prometaphase or metaphase. Moreover, cells with aberrant chromatin morphology were found after treatment with the JNK inhibitor. The data show, for the first time, that JNK is activated in mitotic progenitor cells of developing retinal tissue, suggesting a new role of JNK in the control of progenitor cell proliferation in the retina.

PMID 22496813


Cytoskeleton proteins previously considered exclusive to Ganglion Cells are transiently expressed by all retinal neuronal precursors

BMC Dev Biol. 2011 Jul 22;11:46.

Gutierrez C, McNally M, Canto-Soler MV. Source Wilmer Eye Institute, Department of Ophthalmology, Johns Hopkins University School of Medicine, 400 N Broadway, Baltimore, MD USA.

Abstract ABSTRACT:

BACKGROUND: Understanding the mechanisms governing cell fate specification remains one of the main challenges in the study of retinal development. In this context, molecular markers that identify specific cell types become crucial tools for the analysis and interpretation of these phenomena. In studies using the developing chick retina, expression of the mid-size neurofilament (NF-M) and a chick-specific microtubule associated protein recognized by the RA4 antibody (MAP(RA4)), have been broadly used to selectively identify ganglion cells and their committed precursors. However, observations in our laboratory suggested that the expression of these proteins may not be restricted to cells of the ganglion cell lineage. Because of its potential significance in the field, we pursued a detailed analysis of the expression of these two molecules in combination with an array of proteins that allowed precise identification of all retinal cell-type precursors throughout the development of the chick retina.

RESULTS: Both, NF-M and MAP(RA4) proteins, showed a dynamic pattern of expression coincident with the progression of retinal cell differentiation. Both proteins were coexpressed spatially and temporally in postmitotic neuronal precursors throughout development. Expression of both proteins was seen in ganglion cell precursors and adult differentiated ganglion cells, but they were also transiently expressed by precursors of the photoreceptor, horizontal, bipolar and amacrine cell lineages.

CONCLUSIONS: We have clearly demonstrated that, contrary to the generally accepted paradigm, expression of NF-M and MAP(RA4) proteins is not exclusive to ganglion cells. Rather, both proteins are transiently expressed by all neuronal retinal progenitors in a developmentally-regulated manner. In addition, MAP(RA4) and NF-M are the first molecules so far characterized that may allow unambiguous identification of postmitotic precursors from the pool of mitotically active progenitors and/or the differentiated cell population during retinogenesis. These results are of significant impact for the field of developmental biology of the retina, since they provide novel and important information for the appropriate design and interpretation of studies on retinal cell differentiation, as well as for the reinterpretation of previously published studies.

PMID 21781303

Neural crest cells organize the eye via TGF-β and canonical Wnt signalling

Nat Commun. 2011 Apr;2:265.

Grocott T, Johnson S, Bailey AP, Streit A. Source Department of Craniofacial Development, King's College London, Guy's Campus, London SE1 9RT, UK.


In vertebrates, the lens and retina arise from different embryonic tissues raising the question of how they are aligned to form a functional eye. Neural crest cells are crucial for this process: in their absence, ectopic lenses develop far from the retina. Here we show, using the chick as a model system, that neural crest-derived transforming growth factor-βs activate both Smad3 and canonical Wnt signalling in the adjacent ectoderm to position the lens next to the retina. They do so by controlling Pax6 activity: although Smad3 may inhibit Pax6 protein function, its sustained downregulation requires transcriptional repression by Wnt-initiated β-catenin. We propose that the same neural crest-dependent signalling mechanism is used repeatedly to integrate different components of the eye and suggest a general role for the neural crest in coordinating central and peripheral parts of the sensory nervous system.

PMID 21468017


Eye morphogenesis and patterning of the optic vesicle

Curr Top Dev Biol. 2010;93:61-84.

Fuhrmann S.

Department of Ophthalmology and Visual Sciences, Moran Eye Center, University of Utah, Salt Lake City, Utah, USA. Abstract Organogenesis of the eye is a multistep process that starts with the formation of optic vesicles followed by invagination of the distal domain of the vesicles and the overlying lens placode resulting in morphogenesis of the optic cup. The late optic vesicle becomes patterned into distinct ocular tissues: the neural retina, retinal pigment epithelium (RPE), and optic stalk. Multiple congenital eye disorders, including anophthalmia or microphthalmia, aniridia, coloboma, and retinal dysplasia, stem from disruptions in embryonic eye development. Thus, it is critical to understand the mechanisms that lead to initial specification and differentiation of ocular tissues. An accumulating number of studies demonstrate that a complex interplay between inductive signals provided by tissue-tissue interactions and cell-intrinsic factors is critical to ensuring proper specification of ocular tissues as well as maintenance of RPE cell fate. While several of the extrinsic and intrinsic determinants have been identified, we are just at the beginning in understanding how these signals are integrated. In addition, we know very little about the actual output of these interactions. In this chapter, we provide an update of the mechanisms controlling the early steps of eye development in vertebrates, with emphasis on optic vesicle evagination, specification of neural retina and RPE at the optic vesicle stage, the process of invagination during morphogenesis of the optic cup, and maintenance of the RPE cell fate.

Copyright © 2010 Elsevier Inc. All rights reserved. PMID 20959163

Rearrangement of retinogeniculate projection patterns after eye-specific segregation in mice

Hayakawa I, Kawasaki H. PLoS One. 2010 Jun 8;5(6):e11001. PMID: 20544023


In utero eye development documented by fetal MR imaging

AJNR Am J Neuroradiol. 2009 Oct;30(9):1787-91. Epub 2009 Jun 18.

Paquette LB, Jackson HA, Tavaré CJ, Miller DA, Panigrahy A. Source Division of Neonatology, Institute of Maternal and Fetal Health, Childrens Hospital Los Angeles, Keck School of Medicine, University of Southern California, Los Angeles, CA 90027, USA. Abstract BACKGROUND AND PURPOSE: To date, very limited attention has been given to ocular abnormalities or growth parameters detected by fetal MR imaging. Our objective was to retrospectively determine the relationship between different parameters of eye development and estimated gestational age in the human fetus by use of fetal MR imaging.

MATERIALS AND METHODS: A retrospective study was performed to measure the transverse diameter, interocular distance, and lens diameter of the globes of 127 fetuses who had a morphologically normal central nervous system. Multiple single-shot T2 fast spin-echo images were obtained with a 1.5T magnet by use of contiguous 3-mm intervals in at least 2 orthogonal planes. Loess curves were fitted to explore the relationship between gestational age and each of the 3 measurements of interest. Different models were compared statistically to determine the model of best fit.

RESULTS: For each variable of interest, the "best" model of eye growth was a quadratic function. Specifically, lens growth seems to plateau after 36 weeks of gestation, interocular distance plateaus after 36 weeks of gestation, and globe growth plateaus after 42 weeks of gestation.

CONCLUSIONS: The lens, orbit, and interocular distance growth of the fetus can be demonstrated on fetal MR imaging. All 3 measurements suggest a quadratic model of growth, which indicates slowing of growth toward the end of gestation.

PMID 19541779

Generation of functional eyes from pluripotent cells

PLoS Biol. 2009 Aug;7(8):e1000174. Epub 2009 Aug 18.

Viczian AS, Solessio EC, Lyou Y, Zuber ME.

Department of Ophthalmology, State University of New York (SUNY) Upstate Medical University, Syracuse, New York, United States of America. Comment in:

PLoS Biol. 2009;7(8):e1000175. Abstract Pluripotent cells such as embryonic stem (ES) and induced pluripotent stem (iPS) cells are the starting point from which to generate organ specific cell types. For example, converting pluripotent cells to retinal cells could provide an opportunity to treat retinal injuries and degenerations. In this study, we used an in vivo strategy to determine if functional retinas could be generated from a defined population of pluripotent Xenopus laevis cells. Animal pole cells isolated from blastula stage embryos are pluripotent. Untreated, these cells formed only epidermis, when transplanted to either the flank or eye field. In contrast, misexpression of seven transcription factors induced the formation of retinal cell types. Induced retinal cells were committed to a retinal lineage as they formed eyes when transplanted to the flanks of developing embryos. When the endogenous eye field was replaced with induced retinal cells, they formed eyes that were molecularly, anatomically, and electrophysiologically similar to normal eyes. Importantly, induced eyes could guide a vision-based behavior. These results suggest the fate of pluripotent cells may be purposely altered to generate multipotent retinal progenitor cells, which differentiate into functional retinal cell classes and form a neural circuitry sufficient for vision.

PMID 19688031

Shaping the vertebrate eye

Martinez-Morales JR, Wittbrodt J. Curr Opin Genet Dev. 2009 Oct;19(5):511-7. Epub 2009 Oct 8. Review. For over a century, the vertebrate eye has served as a paradigm for organogenesis. It forms through a complex sequence of morphogenetic events, involving the lateral evagination of the optic vesicles and their subsequent folding into the optic cups. Through intensive studies by experimental embryologists, anatomical descriptions of the process were available since many decades. Recent genetic and molecular work has illuminated essential features of the stereotyped cellular behaviour driving eye morphogenesis. The first pieces of the molecular machinery operating in each individual progenitor cell have been identified. These studies now set the groundwork for a system-wide approach towards understanding the cellular and molecular mechanisms involved in shaping the vertebrate eye.

PMID 19819125

Progenitor cells of the rod-free area centralis originate in the anterior dorsal optic vesicle

Shin SK, O'Brien KM. BMC Dev Biol. 2009 Nov 25;9:57. PMID: 19939282


The other pigment cell: specification and development of the pigmented epithelium of the vertebrate eye

Bharti K, Nguyen MT, Skuntz S, Bertuzzi S, Arnheiter H. Pigment Cell Res. 2006 Oct;19(5):380-94. Review.

Vertebrate retinal pigment epithelium (RPE) cells are derived from the multipotent optic neuroepithelium, develop in close proximity to the retina, and are indispensible for eye organogenesis and vision. Recent advances in our understanding of RPE development provide evidence for how critical signaling factors operating in dorso-ventral and distal-proximal gradients interact with key transcription factors to specify three distinct domains in the budding optic neuroepithelium: the distal future retina, the proximal future optic stalk/optic nerve, and the dorsal future RPE. Concomitantly with domain specification, the eye primordium progresses from a vesicle to a cup, RPE pigmentation extends towards the ventral side, and the future ciliary body and iris form from the margin zone between RPE and retina. While much has been learned about the molecular networks controlling RPE cell specification, key questions concerning the cell proliferative parameters in RPE and the subsequent morphogenetic events still need to be addressed in greater detail.

PMID 16965267

Genetic aspects of embryonic eye development in vertebrates

Graw J. Dev Genet. 1996;18(3):181-97. Review.

The vertebrate eye comprises tissues from different embryonic origins, e.g., iris and ciliary body are derived from the wall of the diencephalon via optic vesicle and optic cup. Lens and cornea, on the other hand, come from the overlying surface ectoderm. The timely action of transcription factors and inductive signals ensure the correct development of the different eye components. Establishing the genetic basis of eye defects has been an important tool for the detailed analysis of this complex process. One of the main control genes for eye development was discovered by the analysis of the allelic series of the Small eye mouse mutants and characterized as Pax6. It is involved in the interaction between the optic cup and the overlaying ectoderm. The central role for Pax6 in eye development is conserved throughout the animal kingdom as the murine Pax6 gene induces ectopic eyes in transgenic Drosophila despite the obvious diverse organization of the eye in the fruit fly compared to vertebrates. In human, mutations in the PAX6 gene are responsible for aniridia and Peter's anomaly. In addition to Pax6, other mutations affecting the interaction of the optic cup and the lens placode have been documented in the mouse. For the differentiation of the retina from the optic cup several genes are responsible: Mi leads to microphthalmia, if mutated, and encodes for a transcription factor, which is expressed in the melanocytes of the pigmented layer of the retina. In addition, further genes are implicated in the correct development of the retina, e.g., Chx10, Dlx1, GH6, Msx1 and -2, Otx1 and -2, or Wnt7b. Mutations within the retinoblastoma gene (RB1) are responsible for retinal tumors. Knock-out mutants of RB1 exhibit a block of lens differentiation prior to the retinal defect. Besides the influence of Rb1, the lens differentiates under the influence of growth factors (e.g., FGF, IGF, PDGF, TGF), and specific genes become activated encoding cytoskeletal proteins (e.g., filensin, phakinin, vimentin), structural proteins (e.g., crystallins) or membrane proteins (e.g., Mip). The optic nerve originates from the neural retina; ganglion cells grow to the optic stalk, forming the optic nerve. Its retrograde walk to the brain through the rudiment of the optic stalk depends on the correct Pax2 expression.

PMID 8631154


Compound developmental eye disorders following inactivation of TGFbeta signaling in neural-crest stem cells

J Biol. 2005;4(3):11. Epub 2005 Dec 14.

Ittner LM, Wurdak H, Schwerdtfeger K, Kunz T, Ille F, Leveen P, Hjalt TA, Suter U, Karlsson S, Hafezi F, Born W, Sommer L. Source Research Laboratory for Calcium Metabolism, Orthopedic University Hospital Balgrist, CH-8008 Zurich, Switzerland.


BACKGROUND: Development of the eye depends partly on the periocular mesenchyme derived from the neural crest (NC), but the fate of NC cells in mammalian eye development and the signals coordinating the formation of ocular structures are poorly understood.

RESULTS: Here we reveal distinct NC contributions to both anterior and posterior mesenchymal eye structures and show that TGFbeta signaling in these cells is crucial for normal eye development. In the anterior eye, TGFbeta2 released from the lens is required for the expression of transcription factors Pitx2 and Foxc1 in the NC-derived cornea and in the chamber-angle structures of the eye that control intraocular pressure. TGFbeta enhances Foxc1 and induces Pitx2 expression in cell cultures. As in patients carrying mutations in PITX2 and FOXC1, TGFbeta signal inactivation in NC cells leads to ocular defects characteristic of the human disorder Axenfeld-Rieger's anomaly. In the posterior eye, NC cell-specific inactivation of TGFbeta signaling results in a condition reminiscent of the human disorder persistent hyperplastic primary vitreous. As a secondary effect, retinal patterning is also disturbed in mutant mice.

CONCLUSION: In the developing eye the lens acts as a TGFbeta signaling center that controls the development of eye structures derived from the NC. Defective TGFbeta signal transduction interferes with NC-cell differentiation and survival anterior to the lens and with normal tissue morphogenesis and patterning posterior to the lens. The similarity to developmental eye disorders in humans suggests that defective TGFbeta signal modulation in ocular NC derivatives contributes to the pathophysiology of these diseases.

PMID 16403239

Non-vascular smooth muscle cells in the human choroid: distribution, development and further characterization

J Anat. 2005 Oct;207(4):381-90.

May CA.

Department of Anatomy, Medical Faculty Carl Gustav Carus, TU Dresden, Dresden, Germany. Abstract To characterize further non-vascular smooth muscle cells (NVSMC) in the choroid of the human eye, extensive morphological studies were performed including a three-dimensional distribution of NVSMC in the adult human eye and their appearance during development. Whole mounts and sections through the choroid and sclera of eyes of 42 human donors (between the 13th week of gestation and 89 years of age) were stained with antibodies against smooth muscle actin and other markers for smooth muscle cells. On the basis of their morphological localization, three groups of NVSMC could be distinguished in the adult eyes: (a) a semicircular arrangement of NVSMC in the suprachoroid and inner sclera, around the entry of posterior ciliary arteries and nerves; (b) NVSMC parallel to the vessels in the posterior eye segment between the point of entry of the posterior ciliary arteries and the point of exit of the vortex veins; and (c) a dense plaque-like arrangement of NVSMC in the suprachoroid, overlying the foveal region. The last of these groups showed most pronounced interindividual differences. During development, the first NVSMC to be observed at the 20th week of gestation belonged to group b. A complete NVSMC network was first observed in a 6-year-old donor eye. All three groups stained positive for smoothelin, caldesmon and calponin in all localizations. The NVSMC show a distinct distribution that might reflect different aspects of their function in the choroid and suprachoroid. All cells could be histochemically characterized as truly contractile.

PMID 16191166


The harderian gland: a tercentennial review

J Anat. 1994 Aug;185 ( Pt 1):1-49.

Payne AP. Source Department of Anatomy, Glasgow University, Scotland, UK.


The harderian gland was first described in 1694 by Johann Jacob Harder (1656-1711). It occurs in most terrestrial vertebrates and is located within the orbit where, in some species, it is the largest structure. It may be compound tubular or compound tubuloalveolar, and its secretory duct is usually morphologically distinct only after leaving the substance of the gland to open on the surface of the nictitating membrane. The tubules of the gland are formed of a single layer of columnar epithelial cells surrounded by myoepithelial cells. The chief product(s) of the gland varies between different groups of vertebrates, and epithelial cells possess granules or vacuoles whose contents may be mucous, serous or lipid. In rodents, the gland synthesises lipids, porphyrins and indoles. In the case of lipid vacuoles, the gland is unusual in releasing these by an exocytotic mechanism. It is unclear whether the gland can act both as an exocrine and endocrine organ. There is control of gland structure and synthesis through a variety of humoral agents, including gonadal, thyroid and pituitary hormones; in addition there is a rich autonomic innervation and many neuropeptides have been identified. The proposed functions of the gland are remarkably diverse and include the gland being (1) a source of 'saliva', (2) a site of immune response, (3) a photoprotective organ, (4) part of a retinal-pineal axis, (5) a source of pheromones, (6) a source of thermoregulatory lipids, (7) a site of osmoregulation, and (8) a source of growth factors. The gland is discussed in terms of its embryology and phylogeny, and in relation to ecological variables. Several goals of future research are identified.

PMID 7559104


Embryology of the eye and its adnexae

Dev Ophthalmol. 1992;24:1-142.

Barishak YR.

Sackler School of Medicine, University of Tel Aviv, Ramat Gan, Israel.


The embryonal and fetal development of the human eye includes a series of sequential events starting with the fertilization of the ovum and culminating in the birth of a normal baby. Three main periods can be distinguished in the prenatal development of the eye. The first period called embryogenesis is characterized by the establishment of the primary organ rudiments and ends at the end of the 3rd week with the appearance of the optic sulci on both sides of the midline at the expanded cranial end of the still open neural folds. The second period called organogenesis includes the development of the primary organ rudiments and extends till the end of the 8th week. The third period involves the differentiation of each of the primitive organs into a fully or partially active organ and is called differentiation. The period of embryogenesis is characterized by the appearance and migration of the neural crest cells and by the formation of the primary brain vesicles. The period of organogenesis extends from the 4th week till the end of the 8th week. The 4th week shows the closure of the neural canal anteriorly with the subsequent evagination of its lateral wall into optic vesicles, the invagination of the lower nasal wall of the optic vesicle causing the formation of the optic cup, and the development of the lens plate, retinal disk and embryonic fissure. The embryonic fissure extends into the optic stalk which connects the cavity of the optic vesicle with the cavity of the neural canal; the hyaloid artery penetrates into the optic cup through the embryonic fissure. During the 5th week, the optic cup is concluded, and the cells of its external layer acquire pigmentation as a result of contact with developing capillaries in the periocular mesenchyme; these capillaries anastomose with each other and form anteriorly the annular vessel. The lens plate develops into a lens pit and later into a lens vesicle which separates soon thereafter from the surface ectoderm. Inside the optic cup, the hyaloid vessels form the capillaries of the posterior tunica vasculosa lentis and through the capillaries of the lateral tunica vasculosa lentis anastomose with the annular vessel. The primary vitreous forms and the surface ectoderm overlying the lens vesicle differentiates into a primitive corneal epithelium. The facial and orbital structures also develop at this stage. The 6th week shows the incipient differentiation of the inner layer of the optic cup into a sensory retina, the formation of the secondary vitreous, the transformation of the posterior cells of the lens vesicle into primary lens fibers, the development of the periocular vasculature and the appearance of the first eyelid folds and of the anlage of the nasolacrimal duct. However, the dominating factor is the closure of the embryonic fissure.(ABSTRACT TRUNCATED AT 400 WORDS)

PMID 1628748


The Timing and Sequence of Events in the Development of the Human Eye and Ear During the Embryonic Period Proper

Sequence of Events during Early Development of the Human Eye

Stage 10 (ca. 2-3.5 mm; 4-12 pairs of somites; ca. 22 days)

  • The optic primordium and the optic sulcus appear in the prosencephalic fold at 8 pairs of somites (Bartelmez 1922; Bartelmez and Blount 1954; Bartelmez and Dvekahan 1962).
  • The optic primordia meet at the torus opticus, or chiasmatic ridge (Bartelmez and Blount 1954).

Stage 11 (ca. 2.5-4.5 mm; 13-20 pairs of somites; ca. 24 days)

  • The optic evagination is produced at the optic sulcus at about 14 pairs of somites, and the optic ventricle is continuous with that of the forebrain (Streeter 1942, Fig. 6; O’Rahilly 1966, Fig. 3).
  • The lateral wall of the evagination is at first in contact with the surface ectoderm (Bartelmez and Blount 1954).
  • The wall of the optic evagination contributes neural crest to its mesenchymal sheath from about 14-16 pairs of somites onwards (Bartelmez and Blount 1954, plate 5). The sheath then separates the evagination from the overlying ectoderm.
  • The optic evagination constitutes the optic vesicle at approximately 17-19 pairs of somites (O’Rahilly 1966, Fig. 3).
  • The caudal limiting sulcus develops between the optic evagination and the forebrain (O’Rahilly 1966, Fig. 3).

Stage 12 (ca. 3-5 mm; 21~29 somites; ca. 26 days)

  • The optic neural crest reaches its maximal extent and the optic vesicle becomes covered by a complete sheath, giving the appearance of a “frightened hedgehog” (Bartelmez and Blount 1954).

Stage 13 (ca. 4-6 mm; 30 or more pairs of somites; ca. 28 days)

  • The optic vesicle is covered by a basement membrane, and the surface ectoderm is lined by a basement membrane (O’Rahilly 1966, Fig. 10).
  • The retinal disc (future inverted layer of optic cup) and lens disc appear and are in contact (O’Rahilly 1966, Figs. 20 and 21).
  • A marginal zone becomes detectable in the retinal disc (O’Rahi1ly 1966, Fig. 22).
  • The primordia of the lateral and superior recti appear (Gilbert 1957).

Stage 14 (ca. 5—7 mm; ca. 32 days)

  • A uveocapillary lamina (O’Rahilly 1966) becomes defined.
  • The retinal disc is invaginated and so the optic cup is formed (Streeter 1945, Fig. 5; O’Rahilly 1966, Fig. 23).
  • The retinal (“choroid”) fissure is delineated (Streeter 1951, Fig. 2).
  • The inverted layer of the optic cup comprises a terminal bar net (future external limiting membrane), proliferative zone (mitotic phase), primitive zone (intermitotic phase), marginal zone, and an internal limiting membrane (O’Rahilly 1966, Fig. 26). The developing cerebral stratum of the retina is closely comparable to the developing cerebral wall (O’Rahilly 1975, Fig. 9).
  • The lens disc becomes indented and so the lens pit is formed. Cell remnants are extruded into the lens pit (O’Rahilly 1966, Figs. 24 and 25).
  • The oculomotor nerve appears (F. Muller, personal communication).
  • The primordia of the superior rectus and superior oblique appear (Gilbert 1957).
  • Condensations for the insertions of the recti appear peripherally and probably contribute to the sclera later (ibid.).

Stage 15 (ca. 7—9 mm; ca. 33 days)

  • The optic cup at stages 14-16 measures approximately 0.2~0.35 mm in diameter (O’Rahilly and Bossy 1972).
  • Retinal pigment appears in the external layer of the optic cup (O’Rahilly 1966, Fig. 29).
  • The primary vitreous body begins to form in the lentiretinal space (O’Rahilly 1966).
  • The hyaloid artery enters the lentiretinal space through the retinal fisure (ibid.).
  • The lens is surrounded by the lens capsule (O’Rahilly 1966, Fig. 10).
  • The lens pit has closed and so the lens vesicle is formed (Streeter 1945).
  • The lens body appears and consists of early lens fibres (O’Rahilly 1966, Fig. 28).
  • The restored surface ectoderm constitutes the anterior epithelium of the future cornea (O’Rahilly 1966, Fig. 27), which has its own basement membrane.
  • The trochlear and abducent nerves appear (F. Miiller, personal communication).
  • The oculomotor and abducent nerves grow to the respective condensations for their muscles (Gilbert 1957).

Stage 16 (ca. 8-11 mm; ca. 37 days)

  • Eyelid grooves appear (Pearson 1980).
  • The rim of the optic cup is pentagonal (Streeter 1951; Fig. 2; O’Rahilly 1966) and five notches (S, a, b, c, d) are present.
  • The lips of the retinal fissure may be in contact or may even be fused (Streeter 1951, Fig. 2).
  • The optic stalk is definite (O’Rahilly 1966).
  • Perilental blood vessels (tunica vasculosa lentis) are visible (ibid.).
  • The lens cavity is D—shaped in section (O’Rahilly 1966, Fig. 30).
  • The ciliary ganglion is present (Woiniak and O’Rahilly 1980).
  • The trochlear nerve grows to the condensation for the superior oblique (Gilbert 1957).
  • The primordium of the medial rectus and the common primordium of the inferior rectus and inferior oblique appear (Gilbert 1957).

Stage 17 (ca. 11-14 mm; ca. 41 days)

  • Eyelid folds develop at stages 17-19 (Pearson 1980).
  • The optic cup measures approximately 0.5 mm in diameter (O’Rahilly and Bossy 1972).
  • A notch for the retinal fissure may persist anteriorly (Streeter 1951, Fig. 2).
  • An internal neuroblastic layer is formed by internal migration into the marginal zone of the retina (O’Rahilly 1966, Fig. 38). The marginal zone then constitutes the transient fibre layer (of Chievitz) (ibid.).
  • The retina comprises the proliferative zone, external neuroblastic layer, transient fibre layer, and internal neuroblastic layer (ibid.).
  • Radial fibres (of Miiller) appear probably between stages 14 and 17 (ibid.).
  • The cavity of the lens vesicle gradually changes on section from D-shaped to crescentic (O’Rahilly 1966, Figs. 31 and 32).
  • The row of lens nuclei is changing on section from a circle to a D to a nuclear bow (Streeter 1948, Figs. 29, 30, and 32).
  • An instance of cyclopia at stage 16 or 17 has been reported (Mall 1917).

Stage 18 (ca. 13~17 mm; ca. 44 days)

  • The eyelids may begin to be visible, and also the grooves initiating the conjunctival sacs (Streeter 1948).
  • The internal neuroblastic layer of the retina is U—shaped (O’Rahilly 1966).
  • The hyaloid system is well developed (Streeter 1951, Fig. 3).
  • The cavity of the lens vesicle is becoming obliterated by primary lens fibres (Streeter 1948, Fig. 31).
  • Mesenchyme invades the interval between the lens epithelium and the surface ectoderm, and possibly the posterior epithelium of the cornea (the mesothelium of the anterior chamber) is forming (Streeter 1948, Fig. 31).
  • An instance of cyclopia has been described (Orts Llorca 1955).

Stage 19 (ca. 16~18 mm; ca. 48 days)

  • The eyelid folds develop into eyelids and the upper and lower eyelids meet at the lateral canthus (Pearson 1980).
  • The lips of the retinal tissue are temporarily everted near the optic stalk (O’Rahilly 1966, Fig. 45).
  • The internal neuroblastic layer of the retina encircles the entrance of the hyaloid artery to the globe (O’Rahilly 1966, Fig. 12).
  • Ganglion cells give rise to optic nerve fibres (O’Rahilly 1966, Fig. 46).
  • The posterior epithelium of the cornea is distinguishable (O’Rahilly 1966, Fig. 44).

Stage 20 (ca. 18-22 mm; ca. 51 days)

  • The medial canthus is established (Pearson 1980).
  • The optic cup measures approximately 1mm in diameter (O’Rahilly and Bossy 1972).
  • Nerve fibres are clearly visible in the retina and they reach the brain (O’Rahilly 1966).
  • The cavity of the optic stalk is obliterated (O’Rahilly 1966, Fig. 49).
  • The lens cavity is obliterated and a lens suture begins to form (O’Rahilly 1966).
  • The developing cornea comprises the anterior epithelium, an acellular postepithelial layer (future substantia propria), and the posterior epithelium (ibid.).
  • The trochlea for the superior oblique begins to form at stages 20 to 23 (Gilbert 1957).

Stage 21 (ca. 22-24 mm; ca. 52 days)

  • Cells begin to invade the postepithelial layer of the cornea, converting it into the substantia propria (O’Rahilly 1966).
  • The levator palpebrae superioris arises by delamination from the superior rectus at stages 21 to 23 (Gilbert 1957).

Stage 22 (ca. 23~28 mm; ca. 54 days)

  • The eyelids are rapidly encroaching on the globe (Streeter 1951).
  • A scleral condensation is now definite (Gilbert 1957).
  • Bergemeister’s papilla (a clump of cells surrounding the exit of the hyaloid artery from the optic nerve) is present in some eyes (O’Rahilly 1966).
  • The “amas stratifié” (the peripheral condensation of the posterior epithelium), pupillary membrane, and anterior chamber develop (ibid.).
  • The cellular invasion of the postepithelial layer of the cornea is complete centrally in some eyes (ibid.).

Stage 23 (ca. 27-31 mm; ca. 57 days)

  • The eyelids are still open (Streeter 1951, Fig. 76), contrary to the statement of Pearson (1980).
  • The optic cup measures approximately 1.5—2 mm in diameter (O’Rahilly and Bossy 1972) and the lens approximately 0.5-1 mm.
  • The retina comprises the pigmented layer, external limiting membrane, proliferative zone, external neuroblastic layer, transient fibre layer, internal neuroblastic layer, nerve fibre layer, and internal limiting membrane (O’Rahilly 1966, Fig. 53).
  • The secondary vitreous body is forming (O’Rahilly 1966, Fig. 56).
  • Secondary lens fibres are forming (O’Rahilly 1966).
  • The cornea comprises the anterior epithelium and its basement membrane, the substantia propria, and the posterior epithelium (Streeter 1951, Fig. 6; O’Rahilly 1966, Fig. 59).
  • An instance of synophthalmia has been described (Orts Llorca 1955).


Br J Ophthalmol. 1928 Sep;12(9):479-95. THE EARLY DEVELOPMENT OF THE ENDOTHELIUM OF DESCEMET'S MEMBRANE, THE CORNEA AND THE ANTERIOR CHAMBER OF THE EYE. Hagedoorn A. Source Assistant of the University Eye Clinic, Amsterdam.

PMID 18168749


Demonstration of the Development of the Human Eye

Trans Am Ophthalmol Soc. 1922;20:259-60.

Magitot A.

PMID 16692595

The microphotographs to be shown were taken with the Lumiere autochrome plates, which reproduce the natural colors. FirstSeries. A 4mm. embryo. Carmin stain. Appear- anceoftheocularvesicle. Twosectionsofan8mm.embryo; carminstain. Thevesicleofthelens. Largeopticpedicle. Firststageofthedevelopmentoftheretina. Thepigment. A 12 mm. embryo. Iron hematoxylin stain. The optic pedicleclosingup. Theappearanceofthefirstopticfibers. Foursectionsofa22mm. embryo. Magenta-redstain. Thevesicleofthelensfilsup. Developmentoftheganglion- celsoftheretina. Sectionshowingtheglialcoatingofthe hyaloidvesselsoftheeye. Theirisatanearlystageandthe firstappearanceofthelacrimalgland.

SecondSeries.-A60anda90mm. embryo. Development oftheanteriorsegmentandoftheciliarybody. Appearance oftheciliarymuscle. Intheretina,appearance of the bipolar cels. Earlystagesofthelacrimalgland. Thelids temporarilysealedby epithelialcels.

Fetusofthefourthmonth(110mm.). Differentiationof theconesandrodsattheopticpole. Thepupillarymem- braneanditsvessels. Appearanceoftheanteriorchamber.

Fetusofthefifthmonth. Thelidsseparate,theanterior chamberfilsup. Atrophyofthepupillarymembrane. Thickeningofthezonula. Stretchingoutofthevisualcels. Beginningatrophyofthelenticularvessels.

Fetusofthesixthandseventhmonth. Thesestagesshow principally a differentiation of the retina which has spread fromthemaculatotheorbicularisportion. Thelenticular vesselshavedisappeared.

ThirdSeries.-Grown-upconesandrods. Ironhematoxy- linstaining. Theretinaandchoroid. Mannstain. Asec- tionthroughthemacula. Ironhematoxylin. Thepyramidal celsoftheoculomotorius. Cajalstain. Thesensorycels oftheGasserianganglion. Nisslmethod.