Eye formation in the human

embryo An embryo ( ) is the initial stage of development for a multicellular organism. In organisms that reproduce sexually, embryonic development is the part of the life cycle that begins just after fertilization of the female egg cell by the male sp ...

begins at approximately three weeks into embryonic development and continues through the tenth week.Ort, D., David, H.
"Development of the Eye"
Retrieved 22 April 2015. Cells from both the mesodermal and the ectodermal tissues contribute to the formation of the eye. Specifically, the eye is derived from the neuroepithelium, surface

ectoderm The ectoderm is one of the three primary germ layers formed in early embryonic development. It is the outermost layer, and is superficial to the mesoderm (the middle layer) and endoderm (the innermost layer). It emerges and originates from the o ...

, and the extracellular

mesenchyme Mesenchyme () is a type of loosely organized animal embryonic connective tissue of undifferentiated cells that give rise to most tissues, such as skin, blood, or bone. The interactions between mesenchyme and epithelium help to form nearly ever ...

which consists of both the

neural crest The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, ...

and

mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical ...

. Neuroepithelium forms the

retina The retina (; or retinas) is the innermost, photosensitivity, light-sensitive layer of tissue (biology), tissue of the eye of most vertebrates and some Mollusca, molluscs. The optics of the eye create a focus (optics), focused two-dimensional ...

ciliary body The ciliary body is a part of the eye that includes the ciliary muscle, which controls the shape of the lens, and the ciliary epithelium, which produces the aqueous humor. The aqueous humor is produced in the non-pigmented portion of the ciliary ...

, iris, and optic nerves. Surface ectoderm forms the

lens A lens is a transmissive optical device that focuses or disperses a light beam by means of refraction. A simple lens consists of a single piece of transparent material, while a compound lens consists of several simple lenses (''elements'') ...

, corneal epithelium and

eyelid An eyelid ( ) is a thin fold of skin that covers and protects an eye. The levator palpebrae superioris muscle retracts the eyelid, exposing the cornea to the outside, giving vision. This can be either voluntarily or involuntarily. "Palpebral ...

. The extracellular mesenchyme forms the

sclera The sclera, also known as the white of the eye or, in older literature, as the tunica albuginea oculi, is the opaque, fibrous, protective outer layer of the eye containing mainly collagen and some crucial elastic fiber. In the development of t ...

, the corneal

endothelium The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the r ...

and stroma,

blood vessels Blood vessels are the tubular structures of a circulatory system that transport blood throughout many animals’ bodies. Blood vessels transport blood cells, nutrients, and oxygen to most of the tissues of a body. They also take waste an ...

muscles Muscle is a soft tissue, one of the four basic types of animal tissue. There are three types of muscle tissue in vertebrates: skeletal muscle, cardiac muscle, and smooth muscle. Muscle tissue gives skeletal muscles the ability to muscle contra ...

, and vitreous. The

eye An eye is a sensory organ that allows an organism to perceive visual information. It detects light and converts it into electro-chemical impulses in neurons (neurones). It is part of an organism's visual system. In higher organisms, the ey ...

begins to develop as a pair of

optic vesicle The eyes begin to develop as a pair of diverticula (pouches) from the lateral aspects of the forebrain. These diverticula make their appearance before the closure of the anterior end of the neural tube; after the closure of the tube around the 4t ...

s on each side of the forebrain at the end of the fourth week of pregnancy. Optic vesicles are outgrowings of the brain which make contact with the surface

and this contact induces changes necessary for further development of the eye. Through a groove at the bottom of the optic vesicle known as choroid fissure the blood vessels enter the eye. Several layers such as the

neural tube In the developing chordate (including vertebrates), the neural tube is the embryonic precursor to the central nervous system, which is made up of the brain and spinal cord. The neural groove gradually deepens as the neural folds become elevated, ...

surface ectoderm The surface ectoderm, AKA external ectoderm, is one of the two early embryonic divisions of the ectoderm. The other early division of the ectoderm is the neuroectoderm. The surface ectoderm develops into the following structures: *Skin (only th ...

, and

contribute to the development of the eye. Eye development is initiated by the master control gene '' PAX6'', a homeobox gene with known homologues in humans (aniridia), mice (small eye), and ''

Drosophila ''Drosophila'' (), from Ancient Greek δρόσος (''drósos''), meaning "dew", and φίλος (''phílos''), meaning "loving", is a genus of fly, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or p ...

'' (eyeless). The PAX6 gene locus is a transcription factor for the various genes and growth factors involved in eye formation. Eye morphogenesis begins with the

evagination Endodermic evagination relates to the inner germ layers of cells of the very early embryo, from which is formed the lining of the digestive tract, of other internal organs, and of certain glands, implies the extension of a layer of body tissue to f ...

, or outgrowth, of the optic grooves or sulci. These two grooves in the neural folds transform into

optic vesicles The eyes begin to develop as a pair of diverticula (pouches) from the lateral aspects of the forebrain. These diverticula make their appearance before the closure of the anterior end of the neural tube; after the closure of the tube around the 4t ...

with the closure of the neural tube.Fuhrmann, S., Levine, E. M. and Reh, T. A. (2000). "Extraocular mesenchyme patterns the optic vesicle during early eye development in the embryonic chick". Development 127, 4599–4609. The optic vesicles then develop into the optic cup with the inner layer forming the retina and the outer portion forming the retinal pigment epithelium. The middle portion of the optic cup develops into the ciliary body and iris. During the

invagination Invagination is the process of a surface folding in on itself to form a cavity, pouch or tube. In developmental biology, invagination of Epithelium, epithelial sheets occurs in many contexts during Animal embryonic development, embryonic developme ...

of the optic cup, the ectoderm begins to thicken and form the lens placode, which eventually separates from the ectoderm to form the lens vesicle at the open end of the optic cup. Further differentiation and mechanical rearrangement of cells in and around the optic cup gives rise to the fully developed eye.

Sequential inductions

This development is an example of sequential inductions where the organ is formed from three different tissues:

Neural tube ectoderm (neuroectoderm)

First, there is an outpocketing of the neural tube called

. Development of the optic vesicles starts in the 3-week embryo, from a progressively deepening groove in the neural plate called the optic sulcus. Some studies suggest this mechanism is regulated by RX/RAX transcription factor.Fuhrmann, S., “Eye Morphogenesis and Patterning of the Optic Vesicle” Current Topics in Developmental Biology 93, 61-84 (07 October 2010) The proteins Wnt and FGF (fibroblast growth factor) play a part in this early stage and are regulated by another protein called Shisa. As this expands, the rostral neuropore (the exit of the brain cavity out of the embryo) closes and the optic sulcus and the neural plate becomes the optic vesicle. Optic nerves arise from connections of the vesicles to the forebrain.

Neuroectoderm Neuroectoderm (or neural ectoderm or neural tube epithelium) consists of cells derived from the ectoderm. Formation of the neuroectoderm is the first step in the development of the nervous system. The neuroectoderm receives bone morphogenetic pro ...

gives rise to the following compartments of the eye: *

*epithelial lining of

and iris *

optic nerve In neuroanatomy, the optic nerve, also known as the second cranial nerve, cranial nerve II, or simply CN II, is a paired cranial nerve that transmits visual system, visual information from the retina to the brain. In humans, the optic nerve i ...

Surface ectoderm

Lens development is closely related to optic vesicle development. The interaction between the growing vesicle and the ectoderm causes the ectoderm to thicken at that point. This thickened portion of the ectoderm is called the lens placode. Next, the placode invaginates and forms a pouch referred to as the lens pit. Scientists are studying the tension forces necessary for invagination of the lens placode and current research suggests that microfilaments might be present in early retinal cells to allow for invagination behavior. Research has also shown that Rho GTPase dependent filopodia from the precursor lens ectoderm play an important role in the formation of the lens pit.Fuhrmann, Sabine, “Eye Morphogenesis and Patterning of the Optic Vesicle” Current Topics in Developmental Biology 93, 61-84 (07 October 2010) Eventually, the pit becomes completely enclosed. This enclosed structure is the lens vesicle. Studies have shown that lens development requires the presence of the Pax6 gene, which is the master regulatory gene for eye morphogenesis.Hill, M.A. (2015
Embryology Vision - Lens Development
Retrieved April 22, 2015. This master regulatory gene is not necessary for the closely associated optic vesicle development.Adler, R., Canto-Soler, M.V., “Molecular mechanisms of optic vesicle development: Complexities, ambiguities and controversies”, Developmental Biology 305,1,1-13 (1 May 2007) Additionally, Ras activation has been shown to be sufficient for starting lens differentiation, but not enough for its completion. The optic vesicles then begin to form the optic cup. Optic cup morphogenesis is the invagination process occurring after neuroectoderm movement forms the spherical optic vesicle (Phase 1). Invagination is when a tissue folds back on itself. Over the course of approximately 12 hours, the distal end of the optic vesicle inner layer begins to flatten (Phase 2). Over the following 18 hours, both the inner and outer layers begin to flex inward at sharp angles, beginning the formation of a C-shaped edge (Phase 3). The final 18 hours involve continuing this apically convex invagination to form the optic cup . At this point, morphologies such as columnar epithelial cells, pseudo-stratified cells, and apically narrow wedge-shaped cells can be observed.Eiraku et al., "Self-organizing optic-cup morphogenesis in three-dimensional cell culture", Nature 472, 51–56 (07 April 2011) The inner layer of the optic cup is made of neuroepithelium (neural retina), while the outer layer is composed of retinal pigment epithelium (RPE). Experiments have determined that RPE cell differentiation and maintenance requires interaction with neighboring tissues, most likely canonical Wnt signaling, while neural retina differentiation is driven by tissue-autonomous factors. Bone morphogenic proteins (BMPs) are important regulators of optic cup development. In fact, research studies have shown that BMP agonists and antagonists are necessary for precision of optic cup development. Interactions between tissues and signaling pathways also play a major role in morphogenesis of the optic cup. It is of interest to note that research has shown isolating the optic cup from neighboring tissue after completed invagination in tissue culture medium can lead to the development of most major parts of the eye, including photoreceptors, ganglion cells, bipolar cells, horizontal cells, amacrine cells and Muller glia. This indicates that morphogenesis of the optic cup occurs independently of external cues from its environment, including presence of lens. However, the lens is necessary to act as an inducer for the ectoderm to transform it into the

cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...

. Surface ectoderm produces the following parts: *

l epithelium *skin of eyelid

Neural crest

Neural crest The neural crest is a ridge-like structure that is formed transiently between the epidermal ectoderm and neural plate during vertebrate development. Neural crest cells originate from this structure through the epithelial-mesenchymal transition, ...

cells are themselves derived from the ectoderm and lie close to the neural tube: *

Cornea The cornea is the transparency (optics), transparent front part of the eyeball which covers the Iris (anatomy), iris, pupil, and Anterior chamber of eyeball, anterior chamber. Along with the anterior chamber and Lens (anatomy), lens, the cornea ...

Descemet's membrane Descemet's membrane ( or the Descemet membrane) is the basement membrane that lies between the corneal proper substance, also called stroma, and the endothelial layer of the cornea. It is composed of different kinds of collagen (Type IV and VIII ...

and endothelium *connective tissue and bony structure of the orbit

Mesoderm

Mesoderm The mesoderm is the middle layer of the three germ layers that develops during gastrulation in the very early development of the embryo of most animals. The outer layer is the ectoderm, and the inner layer is the endoderm.Langman's Medical ...

contributes to the following structures: *

extraocular muscles The extraocular muscles, or extrinsic ocular muscles, are the seven extrinsic muscles of the eye in human eye, humans and other animals. Six of the extraocular muscles, the four recti muscles, and the superior oblique muscle, superior and inferior ...

endothelial The endothelium (: endothelia) is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the res ...

lining of blood vessels of the eye *blood vessels in

choroid The choroid, also known as the choroidea or choroid coat, is a part of the uvea, the vascular layer of the eye. It contains connective tissues, and lies between the retina and the sclera. The human choroid is thickest at the far extreme rear o ...

*Sclera & Choroid *Vitreous *Suspensory fibres *Cornea: Bowman's membrane and stroma

Developmental cascade

According to Liem et al., the organogenesis of the eye is pointed out as an example of a developmental cascade of inductions. The eye is essentially a derivative of the ectoderm from the somatic ectoderm and neural tube, with a succession of inductions by the chordamesoderm. Chordamesoderm induces the anterior portion of the neural tube to form the precursors of the synapomorphic tripartite brain of vertebrates, and it will form a bulge called the diencephalon. Further induction by the chordamesoderm will form a protrusion: the optic vesicle. This vesicle will be subsequently invaginated by means of further inductions from the chordamesoderm. The optic vesicle will then induce the ectoderm that thickens (lens placode) and further invaginates to a point that detaches from the ectoderm and forms a neurogenic placode by itself. The lens placode is affected by the chordamesoderm making it invaginate and forms the optic cup composed by an inner layer of the neural retina and outer layer of the pigmented retina that will unite and form the optic stalk. The pigmented retina is formed by rods and cones and composed of small cilia typical of the ependymal epithelium of the neural tube. Some cells in the lens vesicle will be fated to form the cornea and the lens vesicle will develop completely to form the definitive lens. Iris is formed from the optic cup cells.

Responsivity of head epidermis

Only the epidermis in the head is competent to respond to the signal from the optic vesicles. Both the optic vesicle and the head epidermis are required for eye development. The competence of the head epidermis to respond to the optic vesicle signals comes from the expression of Pax6 in the epidermis. Pax6 is necessary and sufficient for eye induction. This competence is acquired gradually during

gastrulation Gastrulation is the stage in the early embryonic development of most animals, during which the blastula (a single-layered hollow sphere of cells), or in mammals, the blastocyst, is reorganized into a two-layered or three-layered embryo known as ...

and

neurulation Neurulation refers to the folding process in vertebrate embryos, which includes the transformation of the neural plate into the neural tube. The embryo at this stage is termed the neurula. The process begins when the notochord induces the formati ...

from interactions with the

endoderm Endoderm is the innermost of the three primary germ layers in the very early embryo. The other two layers are the ectoderm (outside layer) and mesoderm (middle layer). Cells migrating inward along the archenteron form the inner layer of the gastr ...

, and

neural plate In embryology, the neural plate is a key Development of the human body, developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, Ectoderm, ectodermal tissue thickens ...

Regulation and inhibition

Sonic hedgehog Sonic hedgehog protein (SHH) is a major signaling molecule of embryonic development in humans and animals, encoded by the ''SHH'' gene. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organoge ...

reduces the expression of Pax6. When Shh is inhibited during development, the domain of expression for Pax6 is expanded and the eyes fail to separate causing

cyclopia Cyclopia (named after the Greek mythology characters cyclopes), also known as alobar holoprosencephaly, is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosen ...

. Overexpression of Shh causes a loss of eye structures.

Retinoic acid Retinoic acid (simplified nomenclature for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that is required for embryonic development, male fertility, regulation of bone growth and immune function. All-''trans ...

generated from

vitamin A Vitamin A is a fat-soluble vitamin that is an essential nutrient. The term "vitamin A" encompasses a group of chemically related organic compounds that includes retinol, retinyl esters, and several provitamin (precursor) carotenoids, most not ...

in the retina plays an essential role in eye development as a secreted paracrine signal which restricts invasion of perioptic mesenchyme around the optic cup.

Vitamin A deficiency Vitamin A deficiency (VAD) or hypovitaminosis A is a lack of vitamin A in blood and tissues. It is common in poorer countries, especially among children and women of reproductive age, but is rarely seen in more developed countries. Vitamin A pla ...

during embryogenesis results in

anterior segment The anterior segment or anterior cavity is the front third of the eye that includes the structures in front of the vitreous humour: the cornea, iris, ciliary body, and lens A lens is a transmissive optical device that focuses or dispers ...

defects (particularly cornea and eyelids) that lead to vision loss or blindness. There is some evidence that

LMX1B LIM homeobox transcription factor 1-beta, also known as LMX1B, is a protein which in humans is encoded by the ''LMX1B'' gene. Function LMX1B is a LIM domain, LIM homeobox transcription factor which plays a central role in Limb development#Dor ...

plays a role in periocular mesenchymal survival.

Additional images

File:Ultrasound Scan ND 083.jpg File:Gray865.png, Optic cup and choroidal fissure seen from below, from a human embryo of about four weeks. File:Gray866.png, Horizontal section through the eye of an eighteen days’ embryo rabbit. X 30. File:Gray867.png, Sagittal section of eye of human embryo of six weeks. File:Gray868.png, Section of developing eye of trout.

References

External links

Development of the Eye: A Series of Inductive Interactions
{{DEFAULTSORT:Eye Development Eye Embryology of nervous system