Optic Cup and Lens Vesicle Formation

Optic Cup and Lens Vesicle

• The developing eye starts as shallow grooves on the sides of the forebrain in the 22-day embryo
• These grooves become optic vesicles through outpocketings as the neural tube closes
• Optic vesicles induce changes in the surface ectoderm, essential for lens formation
• The optic vesicle invaginates, forming a double-walled optic cup
• The space between the inner and outer layers of this cup is initially known as the intraretinal space
• The intraretinal space disappears as the layers appose each other
• Invagination involves the inferior surface forming the choroid fissure
• The hyaloid artery uses the choroid fissure to access the inner eye chamber
• The choroid fissure's lips fuse during the seventh week, creating the pupil

Lens Development

• Cells of the surface ectoderm elongate to form the lens placode
• The lens placode develops into the lens vesicle through invagination
• During the fifth week, the lens vesicle separates from the surface ectoderm
• The lens vesicle lies in the mouth of the optic cup

Retina, Iris, and Ciliary Body

• The outer layer of the optic cup is the pigmented layer of the retina, characterized by pigment granules
• The inner (neural) layer of the optic cup’s posterior four-fifths is the pars optica retinae
• Cells in the pars optica retinae differentiate into photoreceptive rods (120 million) and cones (6-7 million)
• Rods are more sensitive but do not detect color, unlike cones
• Adjacent to the photoreceptive layer is the mantle layer
• The mantle layer gives rise to neurons and supporting cells that creates the outer and inner nuclear layers, and the ganglion cell layer
• A fibrous layer containing nerve cell axons lies on the surface
• Nerve fibers converge toward the optic stalk, which develops into the optic nerve
• Light impulses pass through most retinal layers before reaching the rods and cones
• The anterior fifth of the inner layer is the pars ceca retinae, which remains one cell layer thick
• Pars ceca retinae divides into the pars iridica retinae, forming the inner iris layer, and the pars ciliaris retinae, participating in ciliary body formation

Iris and Ciliary Body Formation

• Loose mesenchyme fills the space between the optic cup and surface epithelium
• The sphincter and dilator pupillae muscles form in this mesenchyme from the optic cup's ectoderm
• The adult iris is formed by the pigment-containing external layer, the unpigmented internal layer of the optic cup, and vascularized connective tissue containing pupillary muscles
• Pars ciliaris retinae has marked folding
• Mesenchyme covers the exterior and forms the ciliary muscle
• A network of elastic fibers, the suspensory ligament or zonula, connects the interior to the lens
• Ciliary muscle contraction controls lens curvature by changing tension

Lens Development Specifics

• Posterior wall cells of the lens vesicle elongate anteriorly, forming long fibers
• The primary lens fibers reach the anterior wall by the end of the seventh week
• Secondary lens fibers are continuously added to the central core, so, lens growth isn't finished at this stage

Choroid, Sclera, and Cornea

• The eye primordium is surrounded by loose mesenchyme at the end of the fifth week
• Mesenchyme differentiates into inner and outer layers
• The inner layer forms the highly vascularized pigmented choroid
• The outer layer develops into the sclera and is continuous with the dura mater around the optic nerve
• Mesenchymal layers differentiate differently on the anterior aspect of the eye
• The anterior chamber is a product of vacuolization and splits the mesenchyme into the iridopupillary membrane and the substantia propria of the cornea
• The anterior chamber is lined by flattened mesenchymal cells
• The cornea consists of:
  • Epithelial layer (surface ectoderm)
  • Substantia propria/stroma (continuous with the sclera)
  • Epithelial layer (borders the anterior chamber)
• The iridopupillary membrane disappears
• The posterior chamber sits between the iris, lens, and ciliary body
• The anterior and posterior chambers are filled with aqueous humor, which is produced by the ciliary process of the ciliary body
• Aqueous humor travels from the posterior to the anterior chamber, providing nutrients to the avascular cornea and lens
• Aqueous humor passes through the scleral venous sinus (canal of Schlemm) at the iridocorneal angle, where it is resorbed into the bloodstream
• Blockage of flow at Schlemm's canal is a cause of glaucoma

Vitreous Body

• Mesenchyme invades the optic cup through the choroid fissure
• Mesenchyme forms the hyaloid vessels (supplying the lens) and a vascular layer on the inner retina surface
• A delicate network of fibers forms between the lens and retina
• The interstitial spaces of this network fill with a transparent gelatinous substance
• The hyaloid vessels obliterate and disappear during fetal life, leaving the hyaloid canal

Optic Nerve Formation

• The optic cup connects to the brain through the optic stalk, featuring the choroid fissure on its ventral surface
• Hyaloid vessels are in the choroid fissure
• Nerve fibers return to the brain, lying among the inner stalk wall cells
• The choroid fissure closes during the seventh week
• A narrow tunnel forms inside the optic stalk
• The inner stalk wall grows due to increasing nerve fibers
• The inner and outer stalk walls fuse
• Inner layer cells provide a network of neuroglia that supports optic nerve fibers
• The optic stalk transforms into the optic nerve
• Its center contains a portion of the hyaloid artery, later the central artery of the retina
• Pia arachnoid and dura surround the optic nerve, continuations of the choroid and sclera

Molecular Regulation

• PAX6 is the primary regulatory gene for eye development
• PAX6 is a transcription factor in the PAX (paired box) family of transcription factors
• Contains a paired domain and a paired-type homeodomain
• Initially expressed in the anterior neural ridge of the neural plate
• The single eye field separates into two optic primordia
• SONIC HEDGEHOG (SHH), expressed in the prechordal plate, signals this separation
• SHH upregulates PAX2 in the center of the eye field
• SHH downregulates PAX6
• PAX2 is expressed in the optic stalks, while PAX6 is expressed in the optic cup and overlying surface ectoderm that forms the lens
• Interactive signals regulate optic cup formation between:
  • Optic vesicle
  • Surrounding mesenchyme
  • Overlying surface ectoderm (lens-forming region)
• Fibroblast growth factors (FGFs) from the surface ectoderm promote neural (inner layer) retina differentiation
• Transforming growth factor b (TGF-b), secreted by mesenchyme, directs formation of the pigmented (outer) retinal layer
• MITF and CHX10 are expressed, directing differentiation of the pigmented and neural layers, respectively
• Lens ectoderm is essential for proper optic cup formation

Lens Differentiation

• Differentiation depends on PAX6
• PAX6 acts in the surface ectoderm to regulate lens development
• PAX6 expression upregulates the transcription factor SOX2
• SOX2 maintains PAX6 expression in the prospective lens ectoderm
• The optic vesicle secretes BMP4
• BMP4 upregulates and maintains SOX2 expression and LMAF
• PAX6 regulates the expression of two homeobox genes, SIX3 and PROX1
• PAX6, SOX2, and LMAF initiate expression of lens crystallin formation genes, including PROX1
• SIX3 regulates crystallin production by inhibiting the crystallin gene
• PAX6, through FOX3, regulates cell proliferation in the lens

Eye Abnormalities

• Coloboma:
  • Choroid fissure fails to close on time during the seventh week
  • Causes a cleft
  • Usually in the iris (coloboma iridis)
  • May extend into the ciliary body, retina, choroid, optic nerve, or eyelids
  • Is a common eye abnormality
  • May be linked to mutations in PAX2
• Renal defects:
  • Mutation in PAX2
  • Are part of the renal coloboma syndrome
• Persistent iridopupillary membrane:
  • Doesn’t resorb during formation of the anterior chamber
• Congenital cataracts:
  • The lens becomes opaque during intrauterine life
  • Usually genetically determined
  • Associated with maternal rubella infection between the fourth and seventh weeks of pregnancy
  • However, after the seventh week of pregnancy, the lens may escape damage
  • May be associated with hearing loss
  • Nearly eradicated in the United States due to the MMR vaccine
• Persistent hyaloid artery:
  • Causes a cord or cyst
  • The distal portion of this vessel degenerates, but the proximal part remains
  • Should be only the central artery of the retina
• Microphthalmia:
  • The eye is too small (two-thirds of normal volume)
  • Results from intrauterine infections (cytomegalovirus and toxoplasmosis)
• Anophthalmia:
  • Absence of the eye
  • Accompanied by severe cranial abnormalities
• Congenital aphakia:
  • Absence of the lens
• Aniridia:
  • Absence of the iris
  • Mutations in PAX6
  • Rare anomalies that result from disturbances in induction and development of tissues responsible for formation of these structures
• Cyclopia and synophthalmia:
  • Eyes are partially or completely fused
  • Defect caused by loss of midline tissue
  • Occurs as early as days 19 to 21 of gestation
  • Underdevelopment of the forebrain and frontonasal prominence
  • Associated with holoprosencephaly
  • Is caused by:
    • Maternal alcohol use
    • Maternal diabetes
    • Mutations in SHH
    • Abnormalities in cholesterol metabolism disrupting SHH signaling