Back To Search Results

Embryology, Eye

Editor: Jeremy Clark Updated: 3/27/2023 8:46:12 PM

Introduction

Perhaps biology faces no greater feat than the generation of a complex, multicellular organism from a single cell origin. The eye quintessentially represents this process through the formation of highly specific cell types, regulated by an intricate network of cellular interactions and genetic interplay of the early embryo. 

Development

Register For Free And Read The Full Article
Get the answers you need instantly with the StatPearls Clinical Decision Support tool. StatPearls spent the last decade developing the largest and most updated Point-of Care resource ever developed. Earn CME/CE by searching and reading articles.
  • Dropdown arrow Search engine and full access to all medical articles
  • Dropdown arrow 10 free questions in your specialty
  • Dropdown arrow Free CME/CE Activities
  • Dropdown arrow Free daily question in your email
  • Dropdown arrow Save favorite articles to your dashboard
  • Dropdown arrow Emails offering discounts

Learn more about a Subscription to StatPearls Point-of-Care

Development

Early Morphogenesis

The appearance of optic grooves (neuroectoderm origin) from the developing forebrain marks the first sign of eye development at week three of gestation (see Figure. Embryology of the Eye).[1] As the neural folds fuse, the optic grooves, induced by surrounding mesenchyme, evaginate forming the optic vesicle. The optic vesicles are hollow diverticula that protrude through the surrounding mesenchyme towards the surface ectoderm. This protrusion not only leads to the eventual formation of the optic stalk (future optic nerve) but also induces changes necessary in the surface ectoderm for lens placode formation. The lens placode invaginates towards the optic vesicle and forms the lens pit. As the pit deepens, it becomes the lens vesicle (Figure 1C). The edges of the lens vesicle approach each other, and the lens is pinched off from the outer surface ectoderm layer. The lens vesicle sinks deeper and drifts from the surface ectoderm where it will come to lie in the optic cup.[2] 

At four weeks gestation, the optic vesicle invaginates and creates the optic cup [1] (Figure 1C) - this will become the retina. Grooves form along the ventral surface of the optic cup and stalk, called retinal (or choroid) fissures, to allow the passage of the hyaloid artery and vein [3][4]. The hyaloid vessels become entrapped in the optic nerve as the optic cup fuses around them. The hyaloid vessels become the central retinal artery and vein. The distal hyaloid vessels, which supplied the developing lens, degenerate in the vitreous body and leave a remnant known as the hyaloid canal [4].

The structures of the eye and its adnexa heavily derive from mesenchyme, particularly neural crest cells. The neural crest contributes to the corneal stroma and endothelium, the ciliary body, the uveal stroma and melanocytes, the sclera, meningeal sheaths, connective tissue of the optic nerve and extraocular muscles, and bones of the orbit [5][6]. Neuroectoderm also contributes as the source of the retina, posterior iris, and optic nerve. Surface ectoderm gives rise to the lens and corneal epithelium [6]. Mesoderm differentiates into vascular endothelium of the eye and the extraocular muscles [7].

Retina and Optic Nerve

The retina emerges as the optic vesicle invaginates and forms the optic cup [8]. The invagination process results in both inner and outer layers, and these layers create an intraretinal space, which later gets obliterated as the two layers come to adjoin each other. The outer layer contains pigment granules and becomes the pigmented layer of the retina. The inner layer differentiates into the neural retina which will contain rod and cone cells - the light-sensing cells of the retina. The axons from the neural retina then project into the optic stalk. The proliferation of axons in the optic stalk lumen causes obliteration of the lumen. As a result, it forms the optic nerve [9].

Iris and Ciliary Body

The iris and ciliary body derive from the anterior-most tip of the optic cup [10]. The iris is composed of an external layer containing pigment, an unpigmented layer, and a vascularized layer of pupillary muscles. The margins of the optic cup extend towards the location of the pupil forming the iris. The optic cup inner wall gives rise to the posterior iris pigment epithelium. The optic cup outer wall gives rise to the anterior pigment epithelium [11]. Smooth muscle markers are identifiable on the extending cells, which will form the dilator pupillae and sphincter pupillae muscles. The ciliary epithelium also emerges from the anterior tip of the optic cup. Importantly, the ciliary epithelium will secrete fibrillins that contribute to the suspensory ligaments of the lens. The ciliary muscle, which is responsible for lens accommodation, emerges from mesenchymal cells [12].

Lens

As the optic vesicle emerges, it induces the overlying surface ectoderm to differentiate into the lens placode. The lens placode then invaginates, eventually separating from the surface ectoderm and becoming the lens vesicle [4]. The lens vesicle moves towards the cavity created by the optic cup [1][8]. As the lens vesicle settles into the cavity, the hyaloid artery passes through the retinal fissure. It will supply the developing lens and the inner layer of the optic cup before later regressing [4]. The lens vesicle then matures into the lens proper as tall columnar cells on the posterior aspect of the lens vesicle lose their nuclei and lengthen, forming primary lens fibers [13]. Primary lens fibers are transparent due to the expression of ordered crystalline proteins [2]. The cavity of the lens vesicle obliterates because of primary lens fiber proliferation [4]. The hyaloid artery regresses as the anterior chamber forms, and the lens gets nourished by the aqueous humor. Interestingly, no vitreous hemorrhage occurs during regression, suggesting blood flow has ceased before regression begins [14]. Another important aspect of the lens is the lens capsule. The lens capsule forms as the lens vesicle becomes surrounded by the basement membrane as a result of the invagination from the surface ectoderm. Because of the lens capsule, the lens is an immune-privileged organ. The capsule offers pathogen protection while still allowing the passage of solutes and water [15].

Vitreous

In the mature eye, the vitreous serves to maintain the shape of the globe as well as secure the retina in place. During development, mesenchyme invades the optic cup through the retinal fissures. Among other things, this mesenchyme forms the primary vitreous body, which becomes entrapped as the retinal fissures close and seal off the optic cup. The primary vitreous body loses its vasculature, developing into an acellular gel known as the secondary vitreous body. Finally, the tertiary vitreous forms, giving rise to suspension fibers of the lens [1][16]. In the vitreous' process of becoming avascular, the hyaloid artery regresses and a vestigial structure notable in the mature eye forms - the hyaloid canal [4].

Choroid & Sclera

The developing eye begins to take on the mature form with the formation of the choroid and sclera. Development of the choroid, the vascular layer that supplies the outer retina, begins during the sixth to seventh weeks as the outer retinal pigment epithelium of the optic cup induces surrounding mesenchyme [16]. At week 12, capillaries are visible tracing the retinal pigment epithelium, followed by arterioles and venules at week 15. By week 22, arteries and veins resembling the adult eye are apparent [17]. The sclera, an outer fibrous layer of the eye continuous with the dura mater, is also induced from para-ocular mesenchyme and forms exteriorly to the choroid. The sclera contributes to the stromal layer of the cornea [16].

Cornea

The cornea, a clear portion of the outer eye, allows the passage of light into the eye and provides a large component of refraction. There are three major layers to the cornea: external corneal epithelium, derived from surface ectoderm, the central stroma layer derived from mesenchyme, and interior endothelium derived from neural crest cells [6]. After the lens vesicle departs from the surface ectoderm, the intervening space fills with mesenchyme (continuous with scleral mesenchyme). The lens vesicle induces the development of the cornea, resulting in a transparent, avascular structure [18]. Importantly, keratocytes, derived from stromal mesenchyme, produce a highly organized collagen matrix necessary for transparency and refraction [6].

Eyelids

At approximately week six of gestation the eyelids begin to form, deriving from surface ectoderm and mesenchyme. The surface ectoderm contributes to the epidermis anteriorly and palpebral conjunctiva posteriorly. Between the epidermis and palpebral conjunctiva is a core of mesenchymal tissue which forms the orbicularis oculi muscle. It is the accumulation of neural crest mesenchyme at the lateral margin of the optic cup that induces the appendage-like growth of the eyelids, covering the globe [6]. Interestingly, as the superior and inferior lid grow to cover the front of the eye, they fuse with an epithelial plug (Figure 1E). The lids remained fused, separating between the fifth and seventh months of development [19]. Eyelashes and glands will develop from surface ectoderm [1].

Lacrimal Gland

The lacrimal gland is believed to arise during the seventh week of gestation and will come to position itself in the superolateral position of the orbit [7]. In humans, there is debate about its precise cellular origins. Suggestions are that glandular parenchyma derives from the epithelium and surrounding mesenchyme. Development of the lacrimal gland has been described in a triphasic process:

  1. The presumptive glandular stage: Thickening of the superior fornix epithelium and surrounding mesenchymal condensation
  2. The bud stage: Appearance of nodules through the formation of lumina within epithelial buds
  3. Glandular maturity stage: Appearance of adulthood features (beginning week 9) and continued maturation[20]

Recent work also shows a developmental role for myoepithelial cells (MECs). MECs may provide a communicative medium for epithelial and mesenchymal cells, which their physical location between acinar epithelial cells and the basement membrane reinforces [21].

Molecular Level

Recent work in eye embryology has begun to elucidate the complex orchestration of numerous gene products necessary for proper eye development. Among the most notable of these are PAX6, PAX2, sonic hedgehog (SHH), and Rx. Throughout this interplay the importance not only of accurate products but also of accurate gene dosage cannot be overlooked: both deleterious and over-expressive mutations have been shown to result in eye malformations [22].

PAX6 is expressed at the anterior neural plate, indicating the eye field. At this stage, the eye field has not yet been divided to create two globes. The division of the eye field is accomplished by sonic hedgehog (SHH), which is responsible for central nervous system polarity [23]SHH divides the eye field via the division of the forebrain from which the optic vesicles arise. SHH also upregulates the expression of PAX2 [24]PAX2 will become restricted in its expression to the proximal optic vesicle and be essential for optic stalk formation as well as the closure of the retinal fissures [25]Rx is also expressed in the anterior neural plate and will continue to express in the optic vesicles. Rx plays a critical role in spatial patterning and morphogenesis of the optic vesicle. Additionally, Rx is essential for optic vesicle evagination and PAX6 expression [8]. Later, Rx becomes localized to the neural retina and may be necessary for retinal differentiation and proliferation [22].

Clinical Significance

The delicate development of the eye is sensitive to embryologic errors. Some examples of congenital eye malformations include anophthalmia, coloboma, cyclopia, cataract, aniridia, detached retina, hyaloid artery persistence, aphakia, and cryptophthalmos. For brevity, the reader is encouraged to review other sources to learn more about these malformations as they have been well-described elsewhere.

Understanding the components of normal embryology will guide disease management and treatment options. This point is evident by the advent of therapeutic stem cell technologies, such as those under development for retinal and lacrimal gland regeneration [26][27]. Thus, there is a bright horizon in eye embryology that may provide therapeutic options to individuals that have exhausted current practice.

Media


(Click Image to Enlarge)
<p>Embryology of the Eye</p>

Embryology of the Eye


Contributed by S Bhimji, MD

References


[1]

Edward DP, Kaufman LM. Anatomy, development, and physiology of the visual system. Pediatric clinics of North America. 2003 Feb:50(1):1-23     [PubMed PMID: 12713101]


[2]

Wormstone IM, Wride MA. The ocular lens: a classic model for development, physiology and disease. Philosophical transactions of the Royal Society of London. Series B, Biological sciences. 2011 Apr 27:366(1568):1190-2. doi: 10.1098/rstb.2010.0377. Epub     [PubMed PMID: 21402579]


[3]

Ohuchi H, Sato K, Habuta M, Fujita H, Bando T. Congenital eye anomalies: More mosaic than thought? Congenital anomalies. 2019 May:59(3):56-73. doi: 10.1111/cga.12304. Epub 2018 Aug 21     [PubMed PMID: 30039880]


[4]

Cvekl A, Tamm ER. Anterior eye development and ocular mesenchyme: new insights from mouse models and human diseases. BioEssays : news and reviews in molecular, cellular and developmental biology. 2004 Apr:26(4):374-86     [PubMed PMID: 15057935]

Level 3 (low-level) evidence

[5]

Barishak RY, Ofri R. Embryogenetics: gene control of the embryogenesis of the eye. Veterinary ophthalmology. 2007 May-Jun:10(3):133-6     [PubMed PMID: 17445072]

Level 3 (low-level) evidence

[6]

Creuzet S, Vincent C, Couly G. Neural crest derivatives in ocular and periocular structures. The International journal of developmental biology. 2005:49(2-3):161-71     [PubMed PMID: 15906229]

Level 3 (low-level) evidence

[7]

Tawfik HA, Dutton JJ. Embryologic and Fetal Development of the Human Orbit. Ophthalmic plastic and reconstructive surgery. 2018 Sep/Oct:34(5):405-421. doi: 10.1097/IOP.0000000000001172. Epub     [PubMed PMID: 30134385]


[8]

Fuhrmann S. Eye morphogenesis and patterning of the optic vesicle. Current topics in developmental biology. 2010:93():61-84. doi: 10.1016/B978-0-12-385044-7.00003-5. Epub     [PubMed PMID: 20959163]

Level 3 (low-level) evidence

[9]

Heavner W, Pevny L. Eye development and retinogenesis. Cold Spring Harbor perspectives in biology. 2012 Dec 1:4(12):. doi: 10.1101/cshperspect.a008391. Epub 2012 Dec 1     [PubMed PMID: 23071378]

Level 3 (low-level) evidence

[10]

Davis-Silberman N, Ashery-Padan R. Iris development in vertebrates; genetic and molecular considerations. Brain research. 2008 Feb 4:1192():17-28     [PubMed PMID: 17466284]

Level 3 (low-level) evidence

[11]

Wang X, Xiong K, Lu L, Gu D, Wang S, Chen J, Xiao H, Zhou G. Developmental origin of the posterior pigmented epithelium of iris. Cell biochemistry and biophysics. 2015 Mar:71(2):1067-76. doi: 10.1007/s12013-014-0310-0. Epub     [PubMed PMID: 25344647]

Level 3 (low-level) evidence

[12]

Zhao S, Chen Q, Hung FC, Overbeek PA. BMP signaling is required for development of the ciliary body. Development (Cambridge, England). 2002 Oct:129(19):4435-42     [PubMed PMID: 12223402]

Level 3 (low-level) evidence

[13]

Berthoud VM, Minogue PJ, Osmolak P, Snabb JI, Beyer EC. Roles and regulation of lens epithelial cell connexins. FEBS letters. 2014 Apr 17:588(8):1297-303. doi: 10.1016/j.febslet.2013.12.024. Epub 2014 Jan 14     [PubMed PMID: 24434541]

Level 3 (low-level) evidence

[14]

Taniguchi H, Kitaoka T, Gong H, Amemiya T. Apoptosis of the hyaloid artery in the rat eye. Annals of anatomy = Anatomischer Anzeiger : official organ of the Anatomische Gesellschaft. 1999 Dec:181(6):555-60     [PubMed PMID: 10609053]

Level 3 (low-level) evidence

[15]

Danysh BP, Duncan MK. The lens capsule. Experimental eye research. 2009 Feb:88(2):151-64. doi: 10.1016/j.exer.2008.08.002. Epub 2008 Aug 16     [PubMed PMID: 18773892]

Level 3 (low-level) evidence

[16]

Hoar RM. Embryology of the eye. Environmental health perspectives. 1982 Apr:44():31-4     [PubMed PMID: 7084153]

Level 3 (low-level) evidence

[17]

Sellheyer K. Development of the choroid and related structures. Eye (London, England). 1990:4 ( Pt 2)():255-61     [PubMed PMID: 2199235]


[18]

Zavala J, López Jaime GR, Rodríguez Barrientos CA, Valdez-Garcia J. Corneal endothelium: developmental strategies for regeneration. Eye (London, England). 2013 May:27(5):579-88. doi: 10.1038/eye.2013.15. Epub 2013 Mar 8     [PubMed PMID: 23470788]


[19]

Rubinstein TJ, Weber AC, Traboulsi EI. Molecular biology and genetics of embryonic eyelid development. Ophthalmic genetics. 2016 Sep:37(3):252-9. doi: 10.3109/13816810.2015.1071409. Epub 2016 Feb 11     [PubMed PMID: 26863902]


[20]

de la Cuadra-Blanco C, Peces-Peña MD, Mérida-Velasco JR. Morphogenesis of the human lacrimal gland. Journal of anatomy. 2003 Nov:203(5):531-6     [PubMed PMID: 14635806]


[21]

Makarenkova HP, Dartt DA. Myoepithelial Cells: Their Origin and Function in Lacrimal Gland Morphogenesis, Homeostasis, and Repair. Current molecular biology reports. 2015 Sep 1:1(3):115-123     [PubMed PMID: 26688786]


[22]

Chow RL, Lang RA. Early eye development in vertebrates. Annual review of cell and developmental biology. 2001:17():255-96     [PubMed PMID: 11687490]

Level 3 (low-level) evidence

[23]

Echelard Y, Epstein DJ, St-Jacques B, Shen L, Mohler J, McMahon JA, McMahon AP. Sonic hedgehog, a member of a family of putative signaling molecules, is implicated in the regulation of CNS polarity. Cell. 1993 Dec 31:75(7):1417-30     [PubMed PMID: 7916661]

Level 3 (low-level) evidence

[24]

Zagozewski JL, Zhang Q, Eisenstat DD. Genetic regulation of vertebrate eye development. Clinical genetics. 2014 Nov:86(5):453-60. doi: 10.1111/cge.12493. Epub 2014 Sep 25     [PubMed PMID: 25174583]

Level 3 (low-level) evidence

[25]

Torres M, Gómez-Pardo E, Gruss P. Pax2 contributes to inner ear patterning and optic nerve trajectory. Development (Cambridge, England). 1996 Nov:122(11):3381-91     [PubMed PMID: 8951055]

Level 3 (low-level) evidence

[26]

Mead B, Berry M, Logan A, Scott RA, Leadbeater W, Scheven BA. Stem cell treatment of degenerative eye disease. Stem cell research. 2015 May:14(3):243-57. doi: 10.1016/j.scr.2015.02.003. Epub 2015 Feb 24     [PubMed PMID: 25752437]


[27]

Hirayama M, Kawakita T, Tsubota K, Shimmura S. Challenges and Strategies for Regenerating the Lacrimal Gland. The ocular surface. 2016 Apr:14(2):135-43. doi: 10.1016/j.jtos.2015.11.005. Epub 2015 Dec 29     [PubMed PMID: 26738799]