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Eye formation in the human
embryo An embryo is an initial stage of development of 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 sperm c ...
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 Neuroepithelial cells, or neuroectodermal cells, form the wall of the closed neural tube in early embryonic development. The neuroepithelial cells span the thickness of the tube's wall, connecting with the pial surface and with the ventricular or ...
, 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 every ...
which consists of both the
neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, pe ...
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 Embry ...
. Neuroepithelium forms the
retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then p ...
,
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 Iris most often refers to: *Iris (anatomy), part of the eye *Iris (mythology), a Greek goddess * ''Iris'' (plant), a genus of flowering plants * Iris (color), an ambiguous color term Iris or IRIS may also refer to: Arts and media Fictional ent ...
, and
optic nerves 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 information from the retina to the brain. In humans, the optic nerve is derived from ...
. Surface ectoderm forms the
lens A lens is a transmissive optical device which 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 The corneal epithelium (epithelium corneæ anterior layer) is made up of epithelial tissue and covers the front of the cornea. It acts as a barrier to protect the cornea, resisting the free flow of fluids from the tears, and prevents bacteria fr ...
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. The human eyeli ...
. 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 human eye containing mainly collagen and some crucial elastic fiber. In humans, and some ...
, the corneal
endothelium The endothelium 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 rest of the vess ...
and stroma,
blood vessels The blood vessels are the components of the circulatory system that transport blood throughout the human body. These vessels transport blood cells, nutrients, and oxygen to the tissues of the body. They also take waste and carbon dioxide away f ...
,
muscles Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscle ...
, and vitreous. The
eye Eyes are organs of the visual system. They provide living organisms with vision, the ability to receive and process visual detail, as well as enabling several photo response functions that are independent of vision. Eyes detect light and conv ...
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 4th ...
s on each side of the forebrain at the end of the 4th week of pregnancy. Optic vesicles are outgrowings of the brain which make contact with the 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 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 fold become elevated, ...
,
neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, pe ...
,
surface ectoderm The surface ectoderm (or external ectoderm) forms the following structures: *Skin (only epidermis; dermis is derived from mesoderm) (along with glands, hair, and nails) *Epithelium of the mouth and nasal cavity and glands of the mouth and nasal ca ...
, 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 Embry ...
contribute to the development of the eye. Eye development is initiated by the master control gene ''
PAX6 Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the ''PAX6'' gene. Function PAX6 is a member of the Pax gene family which is responsible for carrying the genet ...
'', a homeobox gene with known homologues in humans (aniridia), mice (small eye), and ''
Drosophila ''Drosophila'' () is a genus of flies, belonging to the family Drosophilidae, whose members are often called "small fruit flies" or (less frequently) pomace flies, vinegar flies, or wine flies, a reference to the characteristic of many species ...
'' (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 4th ...
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 is a mechanism that takes place during gastrulation. This mechanism or cell movement happens mostly in the vegetal ...
of the optic cup, the ectoderm begins to thicken and form the
lens placode The Lens placode is a thickened portion of ectoderm which serves as the precursor to the lens. SOX2 and Pou2f1 POU domain, class 2, transcription factor 1 is a protein that in humans is encoded by the ''POU2F1'' gene. Interactions POU2F1 h ...
, 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
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 4th ...
. 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 ectoderm. Formation of the neuroectoderm is first step in the development of the nervous system. The neuroectoderm receives bone morphogenetic protein-inhi ...
gives rise to the following compartments of the eye: *
retina The retina (from la, rete "net") is the innermost, light-sensitive layer of tissue of the eye of most vertebrates and some molluscs. The optics of the eye create a focused two-dimensional image of the visual world on the retina, which then p ...
*epithelial lining of
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 ...
and
iris Iris most often refers to: *Iris (anatomy), part of the eye *Iris (mythology), a Greek goddess * ''Iris'' (plant), a genus of flowering plants * Iris (color), an ambiguous color term Iris or IRIS may also refer to: Arts and media Fictional ent ...
*
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 information from the retina to the brain. In humans, the optic nerve is derived from ...
s


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 The Lens placode is a thickened portion of ectoderm which serves as the precursor to the lens. SOX2 and Pou2f1 POU domain, class 2, transcription factor 1 is a protein that in humans is encoded by the ''POU2F1'' gene. Interactions POU2F1 h ...
. 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 transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical powe ...
. Surface ectoderm produces the following parts: *
lens A lens is a transmissive optical device which 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''), ...
*
cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical powe ...
l epithelium *skin of eyelid


Neural crest

Neural crest Neural crest cells are a temporary group of cells unique to vertebrates that arise from the embryonic ectoderm germ layer, and in turn give rise to a diverse cell lineage—including melanocytes, craniofacial cartilage and bone, smooth muscle, pe ...
cells are themselves derived from the ectoderm and lie close to the neural tube: *
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 human eye containing mainly collagen and some crucial elastic fiber. In humans, and some ...
*
Cornea The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical powe ...
:
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 Embry ...
contributes to the following structures: *
extraocular muscles The extraocular muscles (extrinsic ocular muscles), are the seven extrinsic muscles of the human eye. Six of the extraocular muscles, the four recti muscles, and the superior and inferior oblique muscles, control movement of the eye and the ...
*
endothelial The endothelium 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 rest of the vessel ...
lining of blood vessels of the eye *blood vessels in
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 human eye containing mainly collagen and some crucial elastic fiber. In humans, and some ...
&
choroid The choroid, also known as the choroidea or choroid coat, is a part of the uvea, the vascular layer of the eye, and contains connective tissues, and lies between the retina and the sclera. The human choroid is thickest at the far extreme rear of ...
*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 Paired box protein Pax-6, also known as aniridia type II protein (AN2) or oculorhombin, is a protein that in humans is encoded by the ''PAX6'' gene. Function PAX6 is a member of the Pax gene family which is responsible for carrying the genet ...
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 multilayered structure known as the gastrula. ...
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 gastru ...
,
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 Embry ...
, and
neural plate The neural plate is a key developmental structure that serves as the basis for the nervous system. Cranial to the primitive node of the embryonic primitive streak, ectodermal tissue thickens and flattens to become the neural plate. The region ante ...
.


Regulation and inhibition

Sonic hedgehog Sonic hedgehog protein (SHH) is encoded for by the ''SHH'' gene. The protein is named after the character ''Sonic the Hedgehog''. This signaling molecule is key in regulating embryonic morphogenesis in all animals. SHH controls organogenesis and ...
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 character cyclopes) is the most extreme form of holoprosencephaly and is a congenital disorder (birth defect) characterized by the failure of the embryonic prosencephalon to properly divide the orbits of ...
. Overexpression of Shh causes a loss of eye structures.
Retinoic acid Retinoic acid (used simplified here for all-''trans''-retinoic acid) is a metabolite of vitamin A1 (all-''trans''-retinol) that mediates the functions of vitamin A1 required for growth and development. All-''trans''-retinoic acid is required in ...
generated from
vitamin A Vitamin A is a fat-soluble vitamin and an essential nutrient for humans. It is a group of organic compounds that includes retinol, retinal (also known as retinaldehyde), retinoic acid, and several provitamin A carotenoids (most notably beta- ...
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. Nyctalopia (ni ...
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.Cassin, B. and Solomon, S. ''Dictionary of Eye Terminology''. Gainesvil ...
defects (particularly cornea and eyelids) that lead to vision loss or blindness. There is some evidence that LMX1B 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


Further reading

*Keith L. Moore and T.V.N. Persaud (2008). ''The developing human—clinical oriented embryology''. 8th edition. USA: Saunders, an imprint of Elsevier Inc. p. 429


External links


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