Embryology of the Eye and Ocular Adnexa

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Figure 1: Neurulation

The development of ocular structures, like embryogenesis as a whole, can best thought of as a series of cascading cellular events governed by a fairly limited set of molecular signals that turn on and off genetic programs. Remarkably, several of these signals have been conserved and recycled throughout evolution and remain essential to the development of all living organisms. Our goal here is to give an general overview of the embryologic concepts pertinent to the field of ophthalmology.

Early Ocular Embryologic Development

The first embryologic event pertinent to ocular development is gastrulation, the process by which the single-layered blastocyst transforms into the trilaminar disc, an area of tissue comprised of all three germ layers (ectoderm, mesoderm, and endoderm).

Shortly after the completion of gastrulation, the neural plate (purple) becomes genetically distinguishable as being neuroectoderm (Figure 1). The neural plate then undergoes neurulation, whereby it invaginates and its opposing edges fuse, forming the neural tube. The optic primordia (orange dots) first appear on the neural tube proximal to the future forebrain. The optic primordia give rise to the optic vesicle (Figures 2 and 3). As the optic vesicle extends outward toward the surface ectoderm, the proximal portion of the vesicle constricts forming the optic stalk (the future optic nerve) and the distal portion invaginates to form the optic cup (the future retina, iris, and ciliary body).

Figure 3: Optic cup & lens vesicle formation

Development of Individual Structures

Eyelids and Conjunctiva

Figure 2: Optic stalk formation

During the fifth week of gestation, the eyelids begin to form from contributions of both neural crest-infiltrated mesenchyme and nearby surface ectoderm. By week seven, two distinct eyelid folds are apparent, and epithelial cells begin to invaginate in the area of the medial lid margins, forming the precursors to the future lacrimal puncta and canaliculi.[1] During week eight, the upper and lower lids proceed to refuse via epithelial cell migration and proliferation.[2] Later, mesenchyme begins to infiltrate the lids to and begin to form the palpebral musculature. In the mid-second trimester, a gradual re-separation of the lids commences, forming the mature palpebral fissure.[3]

Lacrimal Gland

The lacrimal gland begin its development in the seventh week of gestation. Each gland is derived from a set of 15-20 neural crest-derived glandular buds at the superolateral angle of the conjunctival sac.[4] Notably, while the lacrimal gland develops acini and has canalized ducts while in-utero, in a significant minority of infants, reflex tear production does not begin until weeks 1-3 of life.[5]

Lens

Lens formation begins when the optic vesicle induces inward invagination and budding of the overlying surface ectoderm to form the lens vesicle (Figure 3).[6] Lens development is supplied nutrients via derivatives of the hyaloid artery. Later, after hyaloid artery regression, lens nourishment comes from the aqueous humor.

Figure 4: Corneal development

Cornea

The mature cornea is composed of three layers (epithelium, stroma, and endothelium). Each layer has distinct embryologic origins. The corneal epithelium is a derivative of surface ectoderm proximal to the developing lens (Figure 3). The corneal stroma and endothelium, along with a litany of other structures of the anterior segment, are derived from successive waves of invading neural crest cells. [7] The mature, transparent cornea is ultimately formed when the mesenchymal-derived stromal keratocytes produce a highly organized stromal collagen matrix.

Iris and Ciliary Body

Figure 5: Optic cup

The iris and ciliary body are a product of the anterior rim of the optic cup (Figure 5). The inner and outer layers of the anterior rim, induced by surrounding mesenchymal development, give rise to the posterior and anterior portions of iris epithelium respectively.[8] The intrinsic muscles of the iris (sphincter pupillae and dilator pupillae) are derived from the surrounding neuroectoderm, whereas the ciliary muscle, which is responsible for changing the shape of the lens, is derived from invading neural crest cells.[9] Neural crest cells also produce the stroma of the iris, which, based on its concentration of melanocytes, largely determines the color of the mature iris.

Vitreous

The vitreous is primarily composed of a gel-like substance called vitreous humor, a mesenchymal derivative. The role of the primary vitreous, the first phase of vitreous development, is to house the hyaloid vasculature as it provides nourishment to the developing anterior segment (Figure 6). As the primary vitreous and hyaloid vasculature regress, they are succeeded by the acellular, avascular secondary vitreous, which ultimately forms the bulk of what is thought of as the mature vitreous. Regression of the primary vitreous leaves behind Cloquet's canal, a vestigial structure that run through the vitreous body from the optic nerve disc to the lens in the mature eye and is sometimes visible in the mature eye.[10] The final step of vitreous development comes when tertiary vitreous form the lens zonules.[11]

Figure 6: Vitreous embryology

Retina

As previously mentioned, the optic cup rim (anterior 1/5) forms the iris and ciliary body. The remaining 4/5ths of the optic cup gives rise to the retina. The optic cup body has two layers with distinct structural destinies. The thinner, outer layer becomes the retinal pigmented epithelium (RPE), while the thicker, inner layer forms the neural retina.[6] Of note, the RPE is the only pigmented tissue in the body not derived from neural crest cells (is instead a derivative of neural ectoderm).

Choroid and Sclera

Figure 5: Early embryogenesis

The choroid and sclera are formed when mesenchyme proximal to the optic cup condenses into two layers, an inner vascular layer (future choroid), and an outer fibrous layer(future sclera).

Extraocular Muscles

Three areas of growth in the developing head, called preotic myotomes, are responsible for the formation of the extraocular muscles (EOMs). Starting very early in development, each has an associated cranial nerve (CNs III, IV, and VI) and it is these nerves that provide the innervation to their respective mature EOM(s).

Orbit

The structures of the bony orbit are primary a product of neural crest linage, along with a few minor contributions from mesoderm and ectoderm.[12] The orbit starts off as a loose network of undifferentiated mesenchymal cells and begin to ossify in the sixth gestational week.[13] With the exception of the sphenoid and the ethmoid bones, the bones of the orbit develop by direct intramembranous ossification rather than by endochondral ossification.[14]

(characterized by a preceding cartilaginous phase).

Big picture: structural embryologic origins
Table 1: Notable genes within ocular embryology
Gene name Gene function(s)
PAX 6 "Master" gene in the development of the eye; mutations are associated with coloboma, microphthalmia, and Peter’s anomaly[15]
SHH Responsible for the division of the eye field into two globes; mutations are associated with cyclopia
PAX 2 Essential for optic stalk formation and the closure of the retinal fissures[16]
Rx Essential for optic vesicle evagination and PAX6 expression, may also play a role in  retinal differentiation and proliferation[6]
BMP4 Induces the surface ectoderm that overlies the optic vesicle to form a lens placode
Nrl Important regulator of rod photoreceptor development

All images were obtained via a creative common license or direct approval from the original creator.

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  12. Cho, R., & Kahana, A. (2021). Embryology of the Orbit. Journal Of Neurological Surgery Part B: Skull Base, 82(01), 002-006.
  13. Tawfik, H., & Dutton, J. (2018). Embryologic and Fetal Development of the Human Orbit. Ophthalmic Plastic & Reconstructive Surgery, 34(5), 405-421.
  14. Kruijt Spanjer, E., Bittermann, G., van Hooijdonk, I., Rosenberg, A., & Gawlitta, D. (2017). Taking the endochondral route to craniomaxillofacial bone regeneration: A logical approach?. Journal Of Cranio-Maxillofacial Surgery, 45(7), 1099-1106.
  15. Zagozewski JL, Zhang Q, Eisenstat DD. Genetic regulation of vertebrate eye development. Clin Genet. 2014 Nov;86(5):453-60.
  16. Torres M, Gómez-Pardo E, Gruss P. Pax2 contributes to inner ear patterning and optic nerve trajectory. Development. 1996 Nov;122(11):3381-91.
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