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REVIEW
1 Department of Developmental Biology and Kent Waldrep Foundation Center for Basic Neuroscience Research on Nerve Growth and Regeneration, University of Texas Southwestern Medical Center, Dallas, Texas 75235, USA; 2 Department of Molecular Neurobiology, Tokyo Metropolitan Institute for Neuroscience, Fuchu, Tokyo 183-8526, Japan
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Abstract |
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 Top Abstract Anatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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[Keywords: Retinal development; degeneration and regeneration; retinal ganglion cells; axon guidance; topographic mapping; neurotrophins; cancer]
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Anatomy of eye development |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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7 wk of development, and proximal parts of the hyaloid vessels persist to form the central artery and vein of the retina, a branch of the ophthalmic artery. Defects in closure of the fissure result in coloboma, defined as defects of the iris, retina, choroid, and optic nerve, depending on their extent. 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. 2). 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.
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The neural retina |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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; Marquardt and Gruss 2002; Hatakeyama and Kageyama 2004). 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 1987; Holt et al. 1988; Wetts and Fraser 1988; Turner et al. 1990). 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 2002; Hatakeyama and Kageyama 2004). It is thought that homeodomain factors regulate layer specificity while bHLH activators determine cell fate within the homeodomain factor-specified layers (Figs. 2, 3). For example, both Math5 and Pax6 are expressed by RGC progenitors and required for RGC formation (Brown et al. 2001; Marquardt et al. 2001; Wang et al. 2001). Adjacent, early progenitor cells that coexpress Math3 and NeuroD (Inoue et al. 2002) together with Pax6/Six3/Prox1 (Dyer et al. 2003) or Pax6/Six3/Lim1 (Liu et al. 2000) adopt the amacrine or horizontal cell fate in the INL. Coexpression of NeuroD/Mash1 and Otx2/Crx may induce photoreceptor development in the ONL (Furukawa et al. 1997). Later, progenitor cells that express Mash1/Math3 with Chx10 differentiate into bipolar cells (Tomita et al. 2000; Hatakeyama et al. 2001). Still other, misexpression studies using retrovirus have shown that bHLH repressors Hes1/Hes5 promote generation of Müller glial cells from later progenitor cells at the expense of neural differentiation (Furukawa et al. 2000; Hojo et al. 2000). Thus, bHLH factors have critical regulatory functions from progenitor cells to each of the emergent differentiated cell types.
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(TGF) superfamily. GDF11 does not affect progenitor proliferation, but controls the duration of expression of various bHLH and homeobox genes including Math5, Pax6, and Prox1 (Fig. 3, arrows). In so doing, GDF11 ultimately controls the temporal window of competence and thus the relative numbers of retinal cell types (Kim et al. 2005). For example, GDF11 down-regulates Math5 expression causing progenitor cells to lose competence to form RGCs. Instead, they now acquire competence to produce later-born cell types. Consistent with this, GDF11-null mice show an increased number of RGCs at the expense of amacrine cells and photoreceptors (Kim et al. 2005). 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 1999; Yang 2004).
During development, nearly half of RGCs experience programmed cell death (PCD) (Perry et al. 1983). 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. 2003). Neurotrophins induce neural cell survival and differentiation during retinal development through the high-affinity tyrosine kinase (Trk) receptors (von Bartheld 1998). Additional reports have suggested that NGF binding to the low-affinity neurotrophin receptor p75 (p75NTR) might induce PCD in the early phase of retinal development (Frade and Barde 1999). There are two periods of cell death in the developing murine retina. The first peak occurs during embryonic days 15–17 (E15–E17), and is the main onset of neurogenesis, neural migration, and initial axon growth. Recent evidence identifies post-mitotic RGCs at the optic nerve exit undergoing p75NTR-induced PCD (Harada et al. 2006). However, retinal morphology, RGC number, and BrdU-positive cell number in p75NTR mutant mice is normal after E15. In chick retina, migrating RGCs from the ventricular to the vitreal surface of the retina express p75NTR, whereas layered RGCs express the high-affinity NGF receptor TrkA, which may switch the proapoptotic signaling of p75NTR into a neurotrophic one (Gonzalez-Hoyuela et al. 2001). In contrast to the chick model, mouse migratory RGCs express TrkA, while stratified RGCs express p75NTR in retina, and RGC number in TrkA mutant mice is normal (Harada et al. 2006). In addition, expression of TGF receptor, which modulates chick RGC number in combination with p75NTR, is absent in mouse RGCs. 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. In the rat, 50% of the total RGC population dies in the first postnatal week soon after reaching their target axons, the SC, and the dLGN (Perry et al. 1983). While BDNF or NT-4/5 injected into the SC promotes the survival of neonatal RGCs (Cui and Harvey 1995; Ma et al. 1998), BDNF or NT-4/5 mutant mice have normal RGC numbers and double-mutant mice show delay in the inner retinal development (Cellerino et al. 1997; Harada et al. 2005). 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. 2004; Teng et al. 2005; Woo et al. 2005) may uncover the detailed mechanisms of RGC number control and axon remodeling.
Adult retinal stem cells
Retinal stem cells can be isolated from the pigmented ciliary margin of the adult mouse and human eyes (Tropepe et al. 2000). 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. 2006). 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. 2005).
Müller glial cells may also have progenitor-like regenerative potential after mild injury and trophic factor stimulation (Ooto et al. 2004; Fischer 2005). Müller cells are thought to carry out many of the functions provided by radial glia, astrocytes, and oligodendrocytes in the CNS (Harada et al. 2000). Thus, the retinogenic potential may be closely related to neurogenic function of the radial glial cells in the cerebral cortex (Campbell and Gotz 2002; Alvarez-Buylla and Lim 2004).
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Retinal polarity |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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; McLaughlin et al. 2003a). 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. 2002). As summarized in Figure 4, the N–T axis is set earlier than the D–V axis. 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. 1994). 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. 1996). Next, two homeobox containing genes, SOHo1 and GH6, are expressed in a nasal-high and temporal-low pattern (Schulte and Cepko 2000). Thereafter, EphA5 and EphA6 are expressed in a high-to-low T–N gradient (Brown et al. 2000).
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). Ventroptin, a ventrally localized BMP4 antagonist, also negatively regulates the dorsalizing effect of BMP4 (Koshiba-Takeuchi et al. 2000; Sakuta et al. 2001). 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. 2000). In contrast, ectopic expression of Shh results in dorsal inhibition of BMP4 and enhanced expression of ventral cVax (Zhang and Yang 2001). The Vax2 transcription factor (mouse homolog of cVax), is expressed ventrally with overlapping timing to that of BMP4. Ectopic Vax2 expression down-regulates dorsalizing factors including BMP4, Tbx5, ephrin-B1, and ephrin-B2, while up-regulating the ventralizing mediators EphB2 and EphB3 (Schulte et al. 1999). 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. 2002).
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. 2000; Sakuta et al. 2001; Mui et al. 2002). For example, Vax2 has a shallow N–T gradient in addition to its strong D–V gradient (Mui et al. 2002). BF1 mutant mice exhibit both N–T and D–V patterning defects associated with ectopic expression of BF2 and specific loss of Shh, respectively (Huh et al. 1999). 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.
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The optic nerve and ganglion cell axon pathfinding |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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; Hallonet et al. 1999). 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. 1999; Dakubo et al. 2003).
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. 1997). 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. 2002). 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 1988; Sugimoto et al. 2001). Type-1 astrocytes are derived from optic stalk neuroepithelium and represent the largest glial cell population in the optic nerve. These astrocytes are thought to provide a structural support for RGC axons and a scaffold for OPC migration (Tsai and Miller 2002). The projecting RGC axons provide Shh signal for expansion of the astrocyte precursor cell population in the embyronic optic nerve (Dakubo et al. 2003) and additional growth/trophic factors for the proliferation of type-1 astrocytes in the first postnatal week (Burne and Raff 1997).
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 2003; Rasband et al. 2003; Mann et al. 2004; Williams et al. 2004). 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. 1992). 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. 2004). 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. 1995). In netrin-1-deficient retinas, many RGC axons fail to exit into the optic nerve, resulting in optic nerve hypoplasia (Deiner et al. 1997). 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. 1997). 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. 1999). In addition to these guidance cues, EphB receptors have redundant functions in RGC axon pathfinding. 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. 2000, 2001). Similar intraretinal guidance errors are not detected in single knockout of EphB1–3 or EphB1; EphB2 double mutants (Williams et al. 2003). Thus, a proper balance of repulsion and attraction helps RGC axons to navigate in the correct direction toward the optic disc.
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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. 2001; Zhu and Parada 2002). The majority (70%) of childhood optic gliomas are associated with the genetic disease Neurofibromatosis type 1 (NF1) (Listernick and Gutmann 1999). NF1 acts as a tumor suppressor by inhibiting Ras activity and suppressing Ras-mediated cell growth. Conditional knockout (Cre/lox) strategies have been employed to model NF1-initiated optic gliomas in mice. 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. 2002; Zhu et al. 2005). 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.
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Retinal axon guidance and formation of the optic chiasm |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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). It is possible that Slit/Robo signaling may define the site of optic chiasm formation. 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. 2002). Similar studies remain to be performed on Robo2 knockout mice (Long et al. 2004). The available data support a "surround repulsion" model, in which Sema5A and Slit proteins acts as a repulsive "guardrail" establishing a corridor through which RGC axons are channeled.
Heparan sulfates (HS) are also implicated in RGC pathfinding. In neuron-specific conditional knockout mice of EXT1, the HS-polymerizing enzyme, RGC axons project ectopically into the contralateral optic nerve (Inatani et al. 2003). These data are reminiscent of Slit1; Slit2 double-mutant phenotypes (Plump et al. 2002). A recent study showed that cell surface HS promotes Slit–Robo binding and is important for the repulsive activities of Slit2 protein (Hu 2001). Moreover, reduction of one allele of EXT1 in Slit2 knockout mutants causes similar axon misguidance at the optic chiasm (Inatani et al. 2003). These results demonstrate a strong dosage-sensitive genetic interaction between Slit2 and EXT1, indicating that HS plays an essential role in Slit-mediated axon guidance at the optic chiasm. In humans, the optic chiasm lies directly above the diaphragma sallae. Anatomic variations, in which the chiasm is situated more anterior (10%) or posterior (10%) are not uncommon. The guidance molecules discussed above may thus affect the precise anatomical location of the human optic chiasm.
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Divergent cues for uncrossed projections at the optic chiasm |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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). The degree of uncrossed axons is <5% in the mouse, but nearly 50% in humans. This arrangement at the level of the optic chiasm is necessary for acquiring high-quality binocular vision and stereopsis. Ephrin-B2 and EphB1 control axon divergence at the optic chiasm (Williams et al. 2003). Ephrin-B2 is expressed in radial glial cells at the optic chiasm concurrent with the development of the ipsilateral projections, and the blockade of ephrin-B2 eliminates the ipsilateral projection in mice. The EphB1 receptor is specifically expressed in RGCs in the mouse ventrotemporal (VT) retina that give rise to the ipsilateral projection (Fig. 5) and EphB1 mutants reveal a strong reduction in the number of ipsilateral projections (Williams et al. 2003). EphB1; EphB2; EphB3 triple mutants exhibit no more severe phenotype compared with the EphB1 single mutant, indicating an absence of redundancy such that only EphB1 may be up-regulated in growth cones as they enter the chiasm region (Williams et al. 2003).
Several regulatory genes expressed in the developing retina indirectly control ipsilateral projections through regulation of ephrin-B2 and/or EphB1. For example, in Vax2-null mice, ephrin-B2 expression is extended to the ventral retina, but EphB2 is almost absent (EphB1 expression was not examined) (Barbieri et al. 2002). In addition to such a molecular dorsalization of the developing retina (see Fig. 4), Vax2 mutant mice were reported to have almost complete absence of ipsilateral projections (Barbieri et al. 2002). This phenotype was not reproduced in an independent study (Mui et al. 2002). Another candidate for regulating ipsilateral projections is the zinc-finger transcription factor Zic2 that is expressed in differentiated VT RGCs when the ipsilateral projection is formed (Herrera et al. 2003). In VT RGCs, Zic2 expression is spatiotemporally identical to that of EphB1 and the loss- and gain-of-function analyses indicate that Zic2 is sufficient to switch the outgrowth behavior of retinal axons from crossed to uncrossed patterns in response to inhibitory cues from chiasm cells. In addition, genetic hypomorphs of Zic2 display reduced ipsilateral projection. The phenotype appears similar to that of EphB1 mutants, although these mice also exhibit abnormal RGC axons that project between the optic nerve and chiasm. These findings suggest that Zic2 may control the ipsilateral projection by directly regulating multiple guidance genes including EphB1. The proportion of Zic2-expressing cells correlates with the spatiotemporal features of the formation of the uncrossed projection in such diverse species as the mouse, ferret, Xenopus, and chick, and reflects the degree of binocularity in each of these species, implicating Zic2 function in patterning binocular vision throughout evolution (Herrera et al. 2003).
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Ephrins and molecular control of topographic mapping |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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; Wilkinson 2000; McLaughlin and O’Leary 2005). In mouse retina, EphA5 and EphA6 are expressed in a decreasing gradient from temporal to nasal axons, while ephrin-A2 and ephrin-A5 from the posterior to the anterior SC (Fig. 6). The EphA–ephrinA repellent interactions between RGCs and the SC, impedes high EphA-expressing RGC axons from terminating in the ligand-rich posterior part of the SC (Fig. 6, blue and black axons) while permitting low EphA-expressing RGCs to invade (Fig. 6, red axons). In ephrin-A2; ephrin-A5 double-mutant mice, both temporal and nasal RGCs exhibit mapping defects, and the ectopic terminations of nasal RGCs are found anterior to their correct P–A sites (Feldheim et al. 2000). These results support the idea that EphA gradients in the retina and ephrin-A gradients in the SC may operate in combination with axon–axon competition in map formation. Graded EphA receptor expression in the SC and ephrinA expression in the retina also influences A–P positioning (Fig. 6). For example, EphA7 shows the strongest anterior-high and posterior-low expression in the SC, but is absent in the retina. A recent study showed that EphA7 is a repellent substrate for retinal axon growth in vitro, and topographic mapping of both temporal and nasal axons is disturbed in EphA7 mutant mice (Rashid et al. 2005). One recent study reported that an external gradient of Engrailed-2, a homeodomain transcription factor, repels growth cones of Xenopus axons originating from the temporal retina, but attracts nasal axons (Brunet et al. 2005). In engrailed-misexpressing chicken tectum, Eph ligand family 1 (ELF-1) and repulsive axon guidance signal (RAGS) that belong to the family of ligands for Eph-related receptor tyrosine kinases are up-regulated (Logan et al. 1996). In addition, axons from nasal retina frequently arborized at various sites including the inappropriate anterior tectum (Itasaki and Nakamura 1996). Taken together, Engrailed-2 may also participate in the formation of P–A axis in the vertebrate SC, possibly by regulating the expression of Eph family members (Drescher et al. 1997).
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; McLaughlin and O’Leary 2005). EphBs are expressed in a low-to-high D–V gradient by RGCs, and ephrin-B1 is expressed in a low-to-high L–M gradient in the SC (Fig. 6). EphB2; EphB3 double mutants exhibit topographically aberrant projections along the L–M axis (Hindges et al. 2002). The phenotype is equivalent or more severe in mice in which the kinase domain and C terminus of EphB2 is replaced with LacZ, indicating that forward signaling dominates over reverse signaling. These findings imply that EphB-expressing axons are attracted medially by ephrin-B1, in contrast to the repulsive effect of ephrin-B2 at the optic chiasm (Williams et al. 2003). As mentioned in the former section, in Vax2-null mice the expression of D–V retinal markers is altered, including a reduced expression of EphB2 and EphB3 in ventral retina, and VT RGCs show a complete shift in their target zones from medial to lateral SC (Barbieri et al. 2002; Mui et al. 2002). The defects in VT RGC mapping in Vax2 mutants are more severe than EphB2; EphB3 double-mutant mice reflecting the transcriptional regulation of Ephs by Vax2 (Hindges et al. 2002). The cell adhesion molecule L1 is transiently expressed by RGC axons during pathfinding and mapping, and L1-null mice have defects in both P–A and L–M mapping in the SC (Demyanenko and Maness 2003). Thus, L1 function is likely required for the accurate performance for EphA and EphB mediated positioning.
Additional work has indicated that in the dLGN, Eph/ephrin gradients also contribute to RGC topographic target recognition and together with neural activity act to control patterning of eye-specific retinogeniculate layers (Feldheim et al. 2000; McLaughlin et al. 2003a; Garel and Rubenstein 2004; Pfeiffenberger et al. 2005). RGC projections from both eyes initially intermingle, but then segregate postnatally and form eye-specific layers in the dLGN. Ephrin-A2 and ephrin-A5 are expressed in ventral–lateral–anterior-high and dorsal–medial–posterior-low gradients, whereas ephrin-A3 is expressed in small amounts in the dLGN. In ephrin-A2; ephrin-A5 double mutants and ephrin-A2; ephrin-A3; ephrin-A5 triple mutants, eye-specific inputs segregate but the shape and location of eye-specific layers are profoundly disrupted (Pfeiffenberger et al. 2005). Mice lacking the 2 subunit of nicotinic acetylcholine receptor do not segregate eye-specific inputs and lack correlated RGC spiking and calcium waves (McLaughlin et al. 2003b). Inhibition of correlated neural activity by a nicotinic acetylcholine receptor antagonist in ephrin-A2; ephrin-A3; ephrin-A5 triple mutants leads to overlapping retinal projections that are located in inappropriate regions of the dLGN, suggesting that regions of the dLGN that are normally occupied by the contralateral eye become competent for innervation from either eye (Pfeiffenberger et al. 2005).
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Thalamocortical (TC) projections |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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). Recent studies have shown that activity-dependent mechanisms may not be required for the generation of topography of somatosensory and visual cortical maps (Crair 1999; Katz and Crowley 2002). These results suggest that activity-independent mechanisms must be required for the generation of topographic maps in the cortex. During development, TC axons grow into the subcortical telencephalon (ST), where postnatally they continue on their paths to the cortex. Recent studies have suggested the requirement of some guidance cues in the ST, which may have a key role in controlling the initial topography of thalamic projections to the neocortex. For example, Ebf1, a bHLH transcription factor that is expressed in the dorsal thalamus (DT), ST, and marginal zone of the cerebral cortex, specifies the mapping of TC axons (Fig. 7). Ebf1 mutant embryos project dLGN axons abnormally into the amygdalar region or become trapped in the ST. Ebf1-null TC axons outside the dLGN reach the cerebral cortex but show a global caudal shift in topography (Garel et al. 2002). This shift occurs in the absence of an apparent change in thalamic or neocortical reorganization, and is preceded by a shift in the positions of thalamic axons in the ST. The Dlx1 and Dlx2 homeodomain transcription factors are expressed in the ventral thalamus and ST, but are absent from the DT and cortical neurons. In Dlx1; Dlx2 double-mutant embryos, some thalamic axons including axons from the dLGN fail to grow and remain in the ST, and the other axons reach the cortex but exhibit a similar shift in topography, as observed in Ebf1 mutants (Garel et al. 2002). On the other hand, EphAs in the thalamus and ephrin-As in the ST are involved in the regulation of TC projections in the somatosensory area in the frontal cortex (Dufour et al. 2003). These findings suggest that various genes affecting the relative positioning of TC axons within the ST may modify the cortical area, including the visual cortex.
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). Infusion of BDNF or blockade of TrkB signaling inhibits the formation of ocular dominance columns in the cat visual cortex (Cabelli et al. 1997); however, eye-specific segregation of visual inputs to the SC and the dLGN is normal in BDNF knockout mice and conditional mutant in which BDNF expression is absent in the CNS (BDNFflox/flox;nestin-Cre mice) (Lyckman et al. 2005). The absence of BDNF might be compensated by other trophic factors such as NT-4/5. NT-3 is specifically expressed in the layer 4 of the cat visual cortex, both before and during the critical period of TC synapse formation (Lein et al. 2000), and in mice is abundant in specific cortical subregions from P0 until early adulthood (8 wk), whereupon it greatly reduces (Vigers et al. 2000). Conditional mutants in which NT-3 is completely deleted in the cerebral cortex result in reduction of TC projections to the visual cortex, and show a phenotype of impaired visual function, which is one of relative cortical blindness (Ma et al. 2002). These findings implicate neurotrophins in the critical stage of precise TC projections to the visual cortex (Fig. 7). Further studies to reveal the detailed function of neurotrophins during the development of the whole visual pathway may provide important information for the progress of therapeutic methods in RGC protection, regeneration, and rearrangement of TC connections. |
Conclusions |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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Acknowledgments |
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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Footnotes |
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E-MAIL luis.parada{at}utsouthwestern.edu; FAX (214) 648-1960. 
Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1504307
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TopAbstractAnatomy of eye developmentThe neural retinaRetinal polarityThe optic nerve and...Retinal axon guidance and...Divergent cues for uncrossed...Ephrins and molecular control...Thalamocortical (TC) projectionsConclusionsAcknowledgmentsReferences |
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