Ocular Size and Shape Regulation During Development

Molecular regulation of visual system development: more than meets the eye

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The retina develops from the walls of the optic cup with the outer, thinner pigmented layer forming the retinal pigment epithelium RPE and the inner, thicker neural layer differentiating into the neural retina. The neural layer contains photoreceptors rods and cones and other neural cell types, such as bipolar and ganglion cells Fig.

The axons of retinal ganglion cells RGCs residing in the surface layer of the neural retina grow proximally into the wall of the optic stalk to the brain, and gradually form the optic nerve. The pathfinding and orientation of the retinal ganglion innervation at the superior colliculus SC or dorsal lateral geniculate nucleus dLGN reflects the stereotypic orientation of the neuronal somata within the retina.

Embryonic lineages that contribute to the eye. Blue Forebrain neuroectoderm; green surface ectoderm; yellow mesoderm; pink neural crest. Note that the layers of the optic cup fuse to form the RPE and the neural retina, and extend anterior to form the ciliary body and iris.

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Retinal cell fates. Homeodomain and bHLH transcription factors cooperate as intrinsic regulators to define the layer specificity and the neuronal cell fate. Hes1 inhibits neuronal differentiation and maintains progenitor cells. Bottom right The relative timing of cell appearance is for mouse development. The cell types are produced in an orderly manner that is generally conserved in vertebrates Cepko ; Marquardt and Gruss ; Hatakeyama and Kageyama During retinogenesis, these seven cell types derive from a common population of retinal progenitor cells residing in the inner layer of the optic cup.

There are four important steps in the process of generating the mature retina from retinal progenitor cells. Retinal progenitor cells must expand through cell division, exit the cell cycle, commit to a particular cell fate, and then execute the differentiation program for the committed cell type. Lineage analyses have revealed that retinal progenitor cells are multipotent and retain their ability to generate different cell types up to the final cell division Turner and Cepko ; Holt et al. As summarized in Table 1 , numerous recent misexpression and loss of function studies have identified that retinal development is controlled primarily by transcription factors of the basic helix—loop—helix bHLH and homeobox families Marquardt and Gruss ; Hatakeyama and Kageyama It is thought that homeodomain factors regulate layer specificity while bHLH activators determine cell fate within the homeodomain factor-specified layers Figs.

Adjacent, early progenitor cells that coexpress Math3 and NeuroD Inoue et al. Thus, bHLH factors have critical regulatory functions from progenitor cells to each of the emergent differentiated cell types. Expression of homeobox and bHLH genes in the retinal progenitor cells. Extrinsic control of transcription factors for retinal cell type specification. GDF11 controls the number of RGCs by suppressing Math5 expression and causing progenitors to acquire competence to produce later-born cell types such as amacrine cells and photoreceptors.

In so doing, GDF11 ultimately controls the temporal window of competence and thus the relative numbers of retinal cell types Kim et al. Instead, they now acquire competence to produce later-born cell types. Proliferation of retinal progenitors may also be partly controlled by extrinsic cues such as ciliary neurotrophic factor CNTF , bone morphogenetic protein BMP , and fibroblast growth factor FGF molecules; however, these effects appear independent of fate and differentiation cues among both early and late progenitor cells Cepko ; Yang Many transcription factors, neurotrophic factors, cell death-regulating factors, and caspases have all been implicated in the regulation of developmental RGC death Isenmann et al.

Neurotrophins induce neural cell survival and differentiation during retinal development through the high-affinity tyrosine kinase Trk receptors von Bartheld There are two periods of cell death in the developing murine retina.

Ocular Phenotype of Fbn2-Null Mice | IOVS | ARVO Journals

The first peak occurs during embryonic days 15—17 E15—E17 , and is the main onset of neurogenesis, neural migration, and initial axon growth. These findings suggest different mechanisms for RGC number control between mouse and chick retina. The second period of retinal PCD coincides with the phase of tectal and thalamic innervation and synapse formation.

Thus, neurotrophins and their receptors seem to be differentially involved in RGC apoptosis according to the developmental stage. Additional studies to determine the functions of both mature neurotrophins and proneurotrophins Nykjaer et al. Retinal stem cells can be isolated from the pigmented ciliary margin of the adult mouse and human eyes Tropepe et al. Although the number is small in the adult ciliary margin, Wnt3a can increase the self-renewal of retinal stem cells via the canonical pathway Inoue et al. In addition, a glycogen synthase kinase3 GSK3 inhibitor mimics the proliferative effect of Wnt3a, which is partly dependent on FGF signaling.

These results may provide a novel therapeutic strategy for in vitro pooling or in vivo activation of retinal stem cells derived from the adult ciliary margin. Thus, the understanding of developmental retinogenesis and its stenotopic molecular codes described above may one day lead to production of specific neuronal subtypes from retinal stem cells as well as embryonic stem cells Ikeda et al.

Thus, the retinogenic potential may be closely related to neurogenic function of the radial glial cells in the cerebral cortex Campbell and Gotz ; Alvarez-Buylla and Lim In addition to the ordered appearance of retinal cell types, another important genetic influence on retinal progenitor cells is their positional identity as reflected in the subsequent organization of polarity and topographic maps.

Although the direct comparison between humans and other species is difficult, several transcription factors have recently been identified that establish nasal—temporal N—T and the dorsal—ventral D—V retinal polarity Peters ; McLaughlin et al. Pax6 has a principal role, since it is required for the normal regulation of both N—T and D—V axis regulatory genes, thus exerting its importance beyond the early development of the eye cup Baumer et al.

First, polarized expression of the two winged-helix transcription factors, brain factor-1 BF1 and BF2, divides the optic stalk and the retina into nasal and temporal domains Hatini et al. Misexpression of BF1 or BF2 results in misprojection on the chick tectum, showing that these transcriptional factors control the positional identity in RGCs along the N—T axis Yuasa et al. Molecular control of retinal polarity. Early in retinal development, BF1 and BF2 mark the nasal and temporal retina. D-V polarity develops soon after N-T polarity is established.

BMP4 expression in the dorsal retina and Shh and Ventroptin in the ventral retina couteract one another. BMP4 activates Tbx5 and represses Vax2. Tbx5 activates ephrin-Bs and suppresses EphBs.

Vax2 enhances the transcription of EphBs and repress ephrin-Bs. Arrows represent transcriptional activation and T-bars indicate transcriptional repression. Once N—T polarity is determined, D—V polarity develops initially through the opposing actions of dorsally restricted BMP4 and ventrally derived sonic hedgehog Shh signals regulating the growth and specification of the optic primordium Zhang and Yang Next, Tbx5, an apparent target of BMP signaling, is expressed in dorsal retina.

Thus, in chick retina, ectopic BMP4 expression expands the Tbx5 field into ventral retina, followed by enhancement of dorsal markers ephrin-B1 and ephrin-B2 and repression of ventral markers cVax see below , EphB2 and EphB3 Koshiba-Takeuchi et al. In contrast, ectopic expression of Shh results in dorsal inhibition of BMP4 and enhanced expression of ventral cVax Zhang and Yang The Vax2 transcription factor mouse homolog of cVax , is expressed ventrally with overlapping timing to that of BMP4. Vax2-null mice have severe defects in D—V organization, and the dorsal-high and ventral-low expression patterns of ephrin-B1 and ephrin-B2 become flattened Mui et al.

To add further complexity, studies have reported that several genes regulating retinal polarity have graded expression patterns that are not limited to a single axial pattern, suggesting an interplay of regulation for both axes Koshiba-Takeuchi et al.

Thus, current understanding places Pax6 at the beginning of a hierarchy that is followed by N—T axis specification followed by D—V alignment. Disruption of preceding regulatory steps apparently has consequences on all subsequent events. The RGC is the only retinal neuron that projects and conveys visual information to the brain. Once retinal polarity is established, RGCs extend axons to the optic nerve head at the central retina, form the optic nerve and chiasm, and establish retinotopic maps in the SC. Here again, Shh signaling appears to hold important roles. Shh is expressed in the center of the prechordal plate and up-regulates Vax1 and Pax2 in the optic stalk.

The induction of these two genes negatively controls the expression of Pax6 in the optic cup Macdonald et al. Later, Shh secreted from RGCs maintains Pax2 in the optic stalk and disc via Vax1 expression, which is necessary for their specification as glial cells Bertuzzi et al. The optic nerve undergoes gliogenesis similar to general CNS gliogenesis.

Oligodendrocyte type-2 astrocyte precursor cells O-2As are born in the floor of the third ventricle and migrate into the optic nerve toward the eye Ono et al. During migration, O-2As differentiate into oligodendrocyte precursor cells OPCs and type-2 astrocyte precursor cells. Migratory direction of OPCs is regulated by attractive guidance molecule netrin-1, secreted from cells concentrated in the optic disc and in the temporal quadrant of the optic nerve Spassky et al.

OPCs are inhibited from migrating into the retina beyond the optic nerve head, while type-2 astrocyte precursor cells distribute in the retina Watanabe and Raff ; Sugimoto et al. Type-1 astrocytes are derived from optic stalk neuroepithelium and represent the largest glial cell population in the optic nerve.

Ocular Size and Shape Regulation During Development

The projecting RGC axons provide Shh signal for expansion of the astrocyte precursor cell population in the embyronic optic nerve Dakubo et al. During the long distance of axon pathfinding, RGC growth cones are navigated by a succession of different guidance cues expressed in their local environment Oster and Sretavan ; Rasband et al. The first pathfinding task for RGCs is to exit the eye through the optic nerve.

Chondroitin sulphate proteoglycan inhibits RGC axon growth and controls the initial direction of axons Brittis et al. As shown in Figure 5 , a ring of chondroitin sulphate prevents RGC axons from spreading toward the peripheral retina, thus confining extension toward the central optic disc. In addition, axon guidance molecules, such as L1, netrin-1, and laminin-1, are involved in retinal axon exit at the optic disc leading to optic nerve formation Mann et al.

L1 is a member of immunoglobulin family of cell adhesion molecules, and blockade of L1 function severely disrupts radial growth cone orientation and rate of outgrowth Brittis et al. In netrindeficient retinas, many RGC axons fail to exit into the optic nerve, resulting in optic nerve hypoplasia Deiner et al. Similar abnormalities are observed in mice mutant for the netrin-1 receptor, deleted in colorectal cancer DCC , which is expressed on RGC axons Deiner et al. Interestingly, laminin-1 changes netrin-1 attraction to repulsion at the entrance of the optic nerve head, which may help steer retinal axons into the optic nerve Hopker et al.

RGC axons from dorsal retina bypass the optic disc in EphB2; EphB3 double mutants, without affecting the expression of other guidance cues Birgbauer et al. Thus, a proper balance of repulsion and attraction helps RGC axons to navigate in the correct direction toward the optic disc.

Vision and the eye’s anatomy

RGC axon guidance. In the retina, axons are repelled from the periphery by chondroitin sulfate. Slits also contribute to positioning the optic chiasm by creating zones of inhibition. The most common tumor of the optic tract is the optic glioma or pilocytic astrocytoma. This is usually a benign WHO type I tumor whose growth can impair visual function. Formation of optic glioma typically occurs in childhood and is connected to abnormal gliogenesis during embryonic and early postnatal periods Maher et al.

NF1 acts as a tumor suppressor by inhibiting Ras activity and suppressing Ras-mediated cell growth. These studies have provided evidence that induction of NF1-associated optic gliomas requires the heterozygous state of nontumor tissues in addition to loss of NF1 in astrocyte lineage Bajenaru et al. Thus, as known for other NF1-associated tumors, amplified paracrine interplay between sources of mitotic stimulus in the microenvironment and the NF1-nullizygous cells may be at the root of tumor induction.

Further studies to reveal the detailed mechanisms in the formation of optic glioma may produce more widespread benefit in the management of NF1. The optic chiasm is the structure where partial contralateral crossover of RGC axons occurs. Netrin-1 likely exerts its attractant influence on RGC axons after they exit the eye Fig. Sema5A is expressed at the optic disc and along the optic nerve, and blockade of Sema5A function causes retinal axons to stray out of the optic nerve bundle Oster et al.

RGCs express Robo2, a receptor for Slit. Slit1 and Slit2 are present in the ventral diencephalon. Individual mouse knockouts of Slit1 or Slit2 show few RGC axon guidance defects but double mutants develop a large additional chiasm anterior to the true chiasm, and many RGC axons project into the contralateral optic nerve and some extend dorsal or lateral to the chiasm Plump et al. Similar studies remain to be performed on Robo2 knockout mice Long et al.

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