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Visual System Development in Vertebrates Introductory article Article Contents . Introduction . The Retina . The Retinal Axon Pathway Eloisa Herrera, Instituto de Neurociencias de Alicante, CSIC-UMH, Alicante, Spain Lynda Erskine, University of Aberdeen, Aberdeen, Scotland, UK Online posting date: 20th September 2013 Based in part on the previous version of this eLS article ‘Visual System Development in Vertebrates’ (2005) by Karl G Johnson, Derryck Shewan and Christine E Holt. The development of a functional visual system involves a complex series of inductive and signalling interactions essential for the formation of the eye and its central connections with the brain. Outpouchings from the forebrain, together with the overlying surface ectoderm and neural crest cells give rise to the major structures of the eye (neural retina, pigmented epithelium, lens and cornea). Central connections between the eye and brain regions that receive direct connections from the eye (visual targets) are formed by the axons of retinal ganglion cells. Attractive and repulsive cues in the extracellular environment guide the retinal axon along specific pathways in the brain. Gradients of signalling molecules, together with spontaneous neural activity, drive a pointto-point mapping of retinal axons in visual targets, ensuring accurate reconstruction of the visual image. The cellular, molecular and inductive mechanisms that sculpt each of these key developmental processes essential for normal visual system development are beginning to be understood. Introduction The ability to see accurately and to interpret the external environment confers an enormous selective advantage on virtually all motile organisms. As a consequence, after the evolution of pigments capable of being excited by light, functional visual systems have evolved using a wide variety of light-bending and light-detecting structures. Although, many structural differences exist between the mature eyes eLS subject area: Developmental Biology How to cite: Herrera, Eloisa; and Erskine, Lynda (September 2013) Visual System Development in Vertebrates. In: eLS. John Wiley & Sons, Ltd: Chichester. DOI: 10.1002/9780470015902.a0000789.pub3 of different vertebrate species, the developmental mechanisms that mould them are well conserved. These include the development of the neural retina from the anterior neural plate, the induction of the lens from the ectoderm overlying the optic vesicle, the navigation of axons from the retina to postsynaptic neurons and the final refinement process to form precise maps in target regions in the brain. The focus of this article is on the mechanisms controlling the development of the eye and its central connections. The Retina Embryonic origin and morphological development The mature vertebrate retina detects and relays light signals from the external environment to specific regions of the brain. It is derived from the neuroepithelium of the anterior neural tube that bulges laterally (evaginates) soon after neural tube closure to give rise to balloon-shaped optic vesicles (Figure 1). The optic vesicles maintain continuity with the neural tube via the optic stalk and continue to evaginate until they reach the overlying skin ectoderm. Contact with the surface ectoderm induces the central part of the optic vesicle to flatten and subsequently fold inwards (invaginate) to form a double-layered structure, termed the optic cup. The inner layer of the optic cup becomes the neural retina and the outer layer forms the pigmented epithelium that covers the back of the retina. The invagination process eventually brings the neural retina into contact with the presumptive retinal pigmented epithelium, obliterating the original lumen of the optic vesicle. The pigment epithelial cells then begin to synthesise large amounts of melanin, a dark pigment that prevents peripheral light from entering the eye, and sinuous processes from these cells envelop the photoreceptors. Concurrent with optic cup formation, the optic stalk diminishes in size to become a narrow bridge of cells linking the eye to the ventral diencephalon. This structure provides the scaffold eLS & 2013, John Wiley & Sons, Ltd. www.els.net 1 Visual System Development in Vertebrates Lens placode Neuroepithelium Epithelium Lens pit Optic vesicle Optic vesicle Optic cup (b) (a) (c) Pigment epithelium Retina Cornea Lens Optic nerve Optic stalk Rostral Lens vesicle (d) Medial (e) Lateral Caudal Figure 1 Development of the vertebrate eye. (a) The lateral neuroepithelium evaginates towards the overlying presumptive lens ectoderm, creating an optic vesicle. (b) When this bulge contacts the overlying ectoderm, it begins to invaginate, while the overlying ectoderm thickens to form a lens placode. (c) Progressive invagination of the neuroepithelium generates the optic cup (d) while the invaginating lens placode forms the lens pit. The presumptive lens tissue eventually buds off from the overlying epithelium to form a lens vesicle, and the neuroepithelium behind the optic cup constricts to form the optic stalk. (e) Differentiation of the neural retina then takes place, and the pigmented epithelium forms around the retina. Axons from retinal ganglion cells at the innermost surface of the retina exit the eye on their way to the brain, forming the optic nerve. along which blood vessels enter the eye and retinal axons travel out of the eye to establish the optic nerve. See also: Eye Anatomy; Eye Development: Gene Control Genetic control of eye development During the early stages of development, a small subset of cells in the anterior neural plate becomes fated to form the retinae. Accumulating evidence indicates that a hierarchy of genes that are strictly regulated in space and time controls eye development. The earliest known genes to be expressed in the eye-forming neuroepithelium include a number of highly conserved transcription factors, such as SIX3, PAX6 and RX1. These genes are first expressed in a discrete region in the most anterior part of the neural plate. Later, this single expression domain separates into two bilateral spots that will form the optic vesicles. Disruptions in the function of these transcription factors cause dramatic retinal defects. For example, mutations in the pax6 gene cause a reduction in eye size, and in severe cases animals lack eyes altogether. Despite Drosophila and 2 vertebrate eyes being anatomically different, many of the genes responsible for controlling the development of the vertebrate eye are also crucial in eye development in the fruit fly Drosophila. The vertebrate SIX3 gene, for example, is a homologue of Drosophila sine oculus, and vertebrate PAX6 is a homologue of fly eyeless. The separation of one medial eye-field into two lateral structures appears to depend on Sonic hedgehog signalling from the mesoderm at the anterior midline, possibly modulated by a transforming growth factor (TGF)b pathway. Studies in zebrafish and mice have demonstrated that the loss of Sonic hedgehog, or the loss of certain members of the TGFb superfamily, can cause a cyclopic phenotype, presumably by blocking the separation of the central eye-field into bilaterally symmetrical spots (Chiang et al., 1996; Müller et al., 2000). See also: Drosophila Eye Development and Photoreceptor Specification; Drosophila Retinal Patterning; Eye Development: Gene Control; Hedgehog Signalling; Inherited Retinal Diseases: Vertebrate Animal Models; Pax Genes: Evolution and Function; Regulation of Neuronal Subtype Identity in the eLS & 2013, John Wiley & Sons, Ltd. www.els.net Visual System Development in Vertebrates Vertebrate Neural Tube (Neuronal Subtype Identity Regulation); Transcription Factors R R R R R R ONL Retinal polarity OPL At the optic cup stage, signalling molecules secreted from the patterning centres induce the expression of specific transcription factors that will establish retinal polarity along the temporal–nasal (T–N) and dorsal–ventral (D– V) axes. The winged-helix transcription factors Foxg1 and Foxd1, expressed along the T–N axis, determine the temporal and the nasal retina, respectively. Soon after T–N polarity is determined, initial D–V polarity develops through the actions of morphogens such as Sonic hedgehog and BMPs. The dorsalising effect of BMP4 appears to be counteracted by ventroptin, a BMP4 antagonist expressed in the ventral retina. Although the direct regulatory interactions are largely unknown, ectopic expression of ventroptin in the dorsal retina represses the expression of BMP4 and the transcription factor Tbx5, both of which are normally expressed in the dorsal retina, and promotes expression of Vax2, the major determinant of ventral retina. See also: Bone Morphogenetic Proteins and Their Receptors; Transcription Factors Lamination: formation of retinal layers The optic vesicle, like the developing neural tube, consists of a morphologically homogeneous population of columnar epithelial cells. During the morphogenetic changes that accompany optic cup formation (Figure 1), the cells in the neural retina divide repeatedly. These proliferating cells typically extend throughout the entire width of the retina, with their nuclei migrating from the outer surface (adjacent to the retinal pigmented epithelium) to the inner (vitreal) surface and back again during the cell cycle, creating a pseudostratified epithelium. After several rounds of division, cells begin to exit from the cell cycle and migrate to their final positions. The order of cell birth dates is well defined in the mammalian retina, with the different classes of cells generated in overlapping waves. The first cells to be born are the retinal ganglion cells (RGCs) that migrate to the vitreal surface and elaborate a single axon and several dendrites (Figure 2). The next neurons to be born are the cones, amacrine cells and horizontal cells, followed by the rods and bipolar cells. Mueller glia, the only nonneuronal cells within the neural retina, are the last cells to differentiate from the precursor cell pool. See also: Drosophila Retinal Patterning; Photoreceptor Cell Development Regulation; Vertebrate Neurogenesis: Cell Polarity As these cells continue to divide and differentiate, they begin to form three layers of cell bodies separated by two plexiform or synaptic layers. The RGC layer lies at the vitreal surface of the retina, and the fibre layer comprising of RGC axons lies superficial to the cell bodies. The inner plexiform layer separates the RGC layer from cells in the inner nuclear layer, which contains amacrine, bipolar, horizontal and Mueller cell bodies, and provides a site for H Mu INL A B I IPL GCL OFL RGC To optic disc Figure 2 Diagram of a section through the vertebrate neural retina. At the top are the photoreceptors (R) in the outer nuclear layer (ONL). Below this is the outer plexiform layer (OPL) where the photoreceptors synapse with cells in the inner nuclear layer (INL) such as horizontal cells (H) or bipolar cells (B). In the inner nuclear layer are amacrine cells (A) and Mueller glia (Mu). The bipolar cells and inner plexiform cells (I) form synaptic connections with retinal ganglion cells (RGC) in the inner plexiform layer (IPL). RGCs, which have their cell bodies located in the ganglion cell layer (GCL), send their axons along the optic fibre layer (OFL) to the optic disc, where they emerge from the back of the eye in the optic nerve (not shown). Vitreal surface down. Adapted with permission from Dowling (1970). & Association for Research in Vision and Ophthalmology. synaptic connections between the cells in these two layers. The outer plexiform layer separates the inner nuclear layer from the outer nuclear layer that contains the photoreceptors. Synaptic connections between the photoreceptors and the bipolar and horizontal cells form in the outer plexiform layer (Figure 2). Thus, the process of lamination separates the retina into three functionally distinct but synaptically connected layers of neurons involved in receiving, integrating and relaying visual information. However, the mechanisms that segregate the cells into their appropriate layers remain unknown. Although often viewed as homogeneous populations, each retinal cell type has multiple subtypes that perform distinct functions and make specific patterns of synaptic connections. Thus, photoreceptors consist of both rods and cones that differ in their sensitivity to light, morphology and distribution in the retina. Moreover, at least 15 different subtypes of RGCs, as well as multiple types of amacrine and bipolar cells have been described. Synaptic connections form between specific subtypes of retinal interneurons and RGCs, with the connections arranged within distinct sublaminae of the inner plexiform layer. The mechanisms controlling the formation of these precise patterns of synaptic connections are beginning to be understood. In the chick retina selective adhesion has been shown to play an important role. Four highly related adhesion molecules (Sidekick-1, Sidekick-2, DSCAM and DSCAML1) are expressed in nonoverlapping subsets of amacrine and RGCs. These molecules bind to themselves, but not to other, even highly related, proteins creating a potential mechanism for the pairing together of appropriate synaptic partners – selective adhesion promotes pairs of cells expressing the same molecule to interact and eLS & 2013, John Wiley & Sons, Ltd. www.els.net 3 Visual System Development in Vertebrates form synapses, whereas cells expressing different proteins do not. In support of this idea, ectopic expression or loss of function of any of these molecules impairs synaptic specificity in the retina, in a pattern consistent with the disruption of a homophilic adhesion ‘code’ between presumptive synaptic pairs (Yamagata and Sanes, 2008). Although an attractive model to date, this adhesion code has not been described in any other species. Indeed in mice carrying mutations in either Dscam or DscamL1 no defects in synaptic specificity have been found. Instead, the main function of DSCAM in the murine retina appears to be to control the regular spacing of neuronal cell bodies and dendrites, ensuring appropriate distribution of the different cell types over the entire retina (Fuerst et al., 2008; Fuerst et al., 2009). The mechanisms that act to constrain the synaptic connections to the plexiform layers and their targeting to specific sublaminae are also beginning to be elucidated. During early postnatal stages in mouse, when the synaptic connections in the retina are beginning to develop, several inhibitory signalling molecules of the semaphorin family (Sema5A, Sema5B and Sema6a), are expressed either in the outer retina bordering the region where the inner plexiform layer will develop or in specific sublaminae of the inner plexifrom layer. In the absence of these molecules, many neurites mistarget resulting in visual function abnormalities (Matsuoka et al., 2011a, 2011b). Thus, inhibitory cues play an important role in the initial targeting of neurites, with local adhesive interactions acting subsequently to control synaptic pairing. See also: Developmental Biology of Synapse Formation; Semaphorins; Synapse Formation The vertebrate lens The vertebrate lens is derived from the ectoderm that overlies the evaginating optic vesicle (Figure 1). After contact with the optic vesicle, the induced ectoderm thickens to form the lens placode, invaginates forming the lens cup and finally pinches off from the surrounding ectoderm forming the lens vesicle. The lens vesicle initially has a large central cavity into which cells from the posterior lens vesicle (the primary lens fibres) elongate. These fibres expand to fill the cavity and terminally differentiate, losing their mitochondria and nuclei, but maintaining a hard, transparent cytoplasm consisting almost exclusively of crystallin proteins. The cells on the anterior side of the lens vesicle continue to divide, producing cells that will differentiate into secondary fibre cells. Eventually, the cells overlying the primary lens fibres become quiescent, and division is restricted to a germinative ring surrounding the central lens. Secondary lens fibres develop continuously in the germinative ring. These cells differentiate similarly to the primary fibre cells, forming concentric layers around the central primary fibres, with the oldest fibres being in the centre of the lens and the youngest fibres at the periphery. See also: Regeneration of the Vertebrate Lens and Other Eye Structures; Synapse Formation 4 The formation of the lens is a classical example of an inductive interaction. In seminal experiments performed in the early 1900s, Hans Spemann first demonstrated the importance of the optic vesicle for lens induction using tissue ablation approaches in amphibians. Cauterisation of the developing optic vesicle before contact with the surface ectoderm resulted in loss of both the eye and the lens. Moreover, in cases where the ablation was incomplete, and a portion of the optic vesicle remained, lenses formed only in those cases where contact occurred between the optic vesicle remnant and surface ectoderm. These findings suggested that contact of the optic vesicle with the surface ectoderm is both necessary and sufficient for lens induction. However, we now know that the situation is actually more complicated, and direct interaction of the optic vesicle and lens forming ectoderm is the final step in a series of sequential inductive interactions that act to restrict head ectoderm towards a lens fate. See also: Lens Induction; Spemann, Hans The vertebrate cornea Contact with the developing lens triggers the differentiation of the overlying ectoderm into the cornea. This ectoderm forms a multilayered structure with a highly complex extracellular matrix. As the basal ectodermal cells begin secreting collagen to form the primary stroma, migrating neural crest cells arrive at the developing cornea and form the corneal endothelium. These cells secrete hyaluronic acid into the extracellular matrix, causing the matrix to swell and allow a second wave of migrating neural crest cells to invade the cornea. These cells secrete collagen type 1 and hyaluronidase, initiating the shrinking of the stroma. The corneal stroma is dehydrated by thyroxine, a hormone from the thyroid gland, and the collagen-rich extracellular matrix becomes the transparent cornea. See also: Extracellular Matrix; Neural Crest: Origin, Migration and Differentiation; Vertebrate Embryo: Patterning the Neural Crest Lineage The Retinal Axon Pathway RGC axon guidance in the retina RGC bodies are situated close to the vitreal surface of the retina and generate long axons that navigate to the optic disc and exit the retina through the optic nerve. A variety of cell adhesion molecules expressed both by RGC axons and the surrounding neuroepithelial cells and the glial endfeet combine with permissive extracellular matrix molecules to support axon growth. But what makes axons set off towards the optic disc (their exit point form the eye) rather than growing elsewhere within the retina? In rodents, a receding ring of a repulsive protein, chondroitin sulphate proteoglycan (CSPG) coincides with initial axon growth, starting close to the centre of the retina, and creating an environment where CSPG is expressed peripheral to the eLS & 2013, John Wiley & Sons, Ltd. www.els.net Visual System Development in Vertebrates first-born RGCs and not centrally. Through inhibitory signalling, this prevents growth towards the retinal periphery, and helps ‘push’ the axons in their correct direction towards the optic disc (Brittis et al., 1992). CSPGs do not act alone to repel axons away from the retinal periphery. Other inhibitory signalling molecules, such as Slit proteins, are localised at relatively higher concentrations in the retinal periphery and, by repelling axons away from the retinal periphery, help ensure that axons normally grow centrally from the outset (Thompson et al., 2006). Conversely, relatively higher expression of attractive signalling molecules, such as Sonic hedgehog, central to the front of growing axons play an opposite role, and are important for promoting growth towards the central retina (Kolpak et al., 2005). Thus, the spatial and temporal localisation and function of axon guidance cues underlie the RGC axon guidance towards the optic disc. See also: Axon Growth; Axon Guidance; Cytoskeleton in Axon Growth; Immunofluorescence; In Situ Hybridization; Knockout and Knock-in Animals; Specific Neural Connection Formation in the Developing Nervous System; Transgenic Mice What induces axons to turn away from the retinal surface and into the optic nerve? Netrin-1, a secreted axon guidance molecule, is expressed in the eye only at the optic disc. In vitro, retinal axons that express the receptor deleted in colorectal cancer (Dcc) can be attracted to a gradient of netrin-1. Mice deficient in Dcc or netrin-1 show optic nerve hypoplasia, as many axons fail to leave the eye and grow haphazardly around the optic disc (Deiner et al., 1997). The chemoattractive effect of netrin-1 on RGC axons depends on the levels of an important signalling molecule, cyclic adenosine monophosphate (cAMP), within the axons. When cAMP levels are high axons turn towards netrin-1, but if cAMP levels are decreased axons are instead repelled by netrin-1. Netrin-1 itself can induce an increase in growth cone cAMP levels, but when laminin-1 is simultaneously detected by the axons the rise in cAMP levels is prevented, and under these circumstances RGC axons are repelled by netrin-1 in vitro. At the optic disc, netrin-1 is expressed all around the RGC axons, but laminin-1 is only expressed on the vitreal side. This spatial distribution could lead to higher cAMP levels within axons on the optic nerve side, leading the axon to preferentially turn into the optic nerve (Höpker et al., 1999). See also: Netrins Development of the optic chiasm The optic chiasm is the midline site where retinal axons from each eye meet and undergo a selective crossing process such that visual information from the right eye projects exclusively to target regions on the left side of the brain, and information from the left eye goes to the right side of the brain. It develops at the midline of the ventral diencephalon (developing hypothalamus) where RGC axons from the two eyes intersect. Developing astrocytes are the predominant cell type in this region, but their morphology varies, such that more stellate astrocytes occupy positions in the lateral region of the optic chiasm, whereas the radial glia form a dense network immediately surrounding the midline where future RGC axon divergence will occur. Differentiating hypothalamic neurons are also present within the optic chiasm before RGC axon invasion. These neurons are some of the earliest to differentiate in the central nervous system, and are arrayed in an inverted ‘V’ shape that demarcates the posterior boundary of the optic chiasm. The precise position of the chiasm is conferred, at least in part, by inhibitory factors, such as the Slit proteins, which surround the fascicles of axons. By creating barriers to axon growth, these inhibitory molecules delimit permissive channels, through which the axons normally grow (Figure 3). In mice or zebrafish lacking Slit proteins or their Roundabout (Robo) receptors, the retinal axons are no longer channelled along their correct pathway and can grow in aberrant directions, including crossing the midline in ectopic locations (Fricke et al., 2001; Plump et al., 2002). Indeed, this widespread ‘straying’ of axons from their normal pathway in the absence of Slit-signalling lead to the name ‘astray’ being given to zebrafish carrying a mutation in robo2, the main Slit receptor expressed by retinal axons. Axon divergence at the optic chiasm The visual world is segregated into two halves at the optic chiasm. Stimulation in the left visual field is transmitted to the right side of the brain, whereas stimulation in the right visual field is conducted to the left side of the brain. Many lower vertebrates have largely nonoverlapping visual fields because their eyes are located on the sides of their heads. In such organisms, axons from the left eye cross the chiasm and project exclusively to the right optic tract, whereas axons from the right eye project into the left optic tract. Primates, and other mammals and birds with forwardfacing eyes, have predominantly overlapping visual fields: an object in the left half of the visual world will stimulate RGCs in the nasal half of the left eye, and in the temporal half of the right eye. Thus, in order to segregate the visual world into two halves, axons must separate at the optic chiasm so that nasal retinal axons project to contralateral structures, whereas the temporal axons project to ipsilateral structures (Figure 3). The proportion of axons remaining in the mature ipsilateral optic tract correlates with the amount of overlap in the visual fields; primate eyes have large overlapping visual fields and approximately 50% of RGC axons cross at the chiasm, whereas in rodents, only a small proportion of RGCs in the ventrotemporal retina send axons to the ipsilateral tract, consistent with the reduced overlap in their visual field. The mechanisms that segregate the visual world at the optic chiasm are beginning to be understood. Ephrin-B, a ligand for the EphB family of receptor tyrosine kinases, is expressed by glial cells at the optic chiasm midline and acts as a repellent signal for ipsilateral RGC axons that express EphB. In frogs, Ephrin-B is upregulated at the midline of the chiasm at metamorphosis. At this stage, a population of ventrotemporal RGCs expressing EphB, begin to project eLS & 2013, John Wiley & Sons, Ltd. www.els.net 5 Visual System Development in Vertebrates Retina Temporal Nasal Nasal -Optic chiasm --- - ++ + + -+ + - -- Temporal ---- Lateral geniculated nucleus Superior colliculus (+) Contralateral axons: Isl2, Nrp1, NrCam, PlexinA1 and Robo Ipsilateral axons: Zic2, EphB1 and Robo Cells sourrounding the optic nerve fascicles: Slits (−) Midline cells: EphrinB2(−), VEGF-A (+) and NrCam/Sema6D (+) Attractive signalling (−) Repulsive signalling Figure 3 Molecular mechanisms underlying axonal guidance at the optic chiasm of mice. RGC axons expressing Robo receptors exit the retina via the optic nerve. Diffusible Slit molecules delimit a repulsion-free corridor that demarcates the point where the optic chiasm must form. Axons from the temporal retina (blue lines) that express the EphB1 receptor (induced by the transcription factor Zic2) are repelled by ephrin-B2 that is expressed by glial cells at the midline. As a consequence of EphB1/ephrin-B2 interaction, ipsilateral axons turn to project to targets in the same side. Contralateral axons (red lines) do not express EphB1 and ignore Ephrin-B2. Instead, because they express Neuropilin1 (Nrp1) they are attracted by VEGF-A expressed at the midline. Additionally, contralateral but not ipsilateral axons express NrCAM and PlexinA1. PlexinA1, NrCAM and Sema6D are also expressed at the midline and interact to help promote midline crossing. Contralateral RGCs express the transcription factor Isl2, although a link between this transcription factor and expression of the crossing axon guidance molecules remains to be established. ipsilaterally, whereas all axons in premetamorphic embryos project contralaterally. If metamorphic RGCs from the ventrotemporal (i.e., ipsilateral-projecting) retina are transplanted into embryonic eyes, their axons now cross the chiasm. Furthermore, precocious expression of Ephrin-B at the embryonic chiasm induces premetamorphic axons to be deflected at the midline (Nakagawa et al., 2000). Similarly, mice in which the gene for EphB1 (expressed specifically by ipsilateral RGCs) has been knocked out have a reduced ipsilateral projection, and when Ephrin-B2 signalling is blocked at the midline of the optic chiasm the ipsilateral projection does not develop (Williams et al., 2003). In general, species with binocular vision express ephrin-B at the chiasm whereas animals 6 without binocularity lack ephrin-B at the chiasm. See also: Ephrins The expression of EphB1 in ipsilaterally projecting RGCs is controlled by the zinc finger transcription factor, Zic2 (Figure 3). Zic2 is expressed in ipsilateral but not in contralateral RGCs. In mice carrying a mutation in this transcription factor the ipsilateral projection does not develop properly. Conversely, ectopic expression of Zic2 in the RGC that normally cross the midline switches the laterality of their axons to project ipsilaterally (Herrera et al., 2003; Garcia-Frigola et al., 2008). Zic2 expression in ventrotemporal retina is conserved both in mammals and amphibians, precisely mirroring the extent of binocularity. Thus, Zic2/EphB/ephrin-B-based axon sorting at the eLS & 2013, John Wiley & Sons, Ltd. www.els.net Visual System Development in Vertebrates chiasm appears to have been conserved through evolution, suggesting that it plays a key role in the decision not to cross the midline. See also: Albinism: Genetics; Electroporation; Transcription Factors More puzzling has been the mechanisms that induce contralateral axons to grow towards and through the chiasm midline. Recently, however, the first growth-promoting factor essential for contralateral growth at the chiasm midline was identified. Surprisingly, this factor was found to be vascular endothelial growth factor (VEGF)-A, a molecule best known for its role in blood vessel development, and not shown previously to play a physiological role in axon outgrowth. VEGF-A is expressed at the chiasm midline and, independent of its role in blood vessels, provides growth-promoting and chemoattractive signals to contralateral retinal axons that express one of its known receptors, neuropilin-1 (Figure 3). In mice carrying a mutation in neuropilin-1 or a form of VEGF-A that cannot signal through neuropilin-1, many axons that would normally project contralaterally fail to cross the midline (Erskine et al., 2011). However, it is unclear currently if the role of VEGF-A in contralateral retinal axon growth is conserved among species. Although neuropilin-1 has been found to play an important role in ensuring contralateral growth at the optic chiasm in zebrafish, the identified ligand in this case is a member of the class 3 semaphorin family of inhibitory signalling molecules (Sakai and Halloran, 2006). Whether VEGF-A also acts in this system, or indeed any species other than mice, has not yet been investigated. A second growth-promoting mechanism, involving a transmembrane semaphorin, Sema6D, has also been identified recently. In mice, Sema6D is expressed at the chiasm midline and in combination with PlexinA1 and NrCAM, which are expressed both on the retinal axons and in their environment, generates an attractive signalling complex that may act in concert with VEGF-A to promote contralateral growth (Kuwajima et al., 2012; Figure 3). See also: Axon Guidance at the Midline RGC targets in the brain: the lateral geniculate nucleus (LGN) and the superior colliculus (SC) After leaving the optic chiasm, and entering either the ipsilateral or contralateral optic tract, retinal axons project to multiple targets in the thalamus and midbrain. In lower vertebrates, the majority of axons terminate in the optic tectum of the midbrain. In mammals, retinal axons project to two main targets, the SC, the tectum homologue and the LGN in the thalamus (Figure 3). Topographical mapping of retinal axons at the visual targets The visual image projected on to the retina is inverted, owing to the shape and refractive properties of the lens. The inverted retinal image is reinverted when transmitted to the brain, without sacrificing detailed or positional information. Each RGC axon terminates in a position within the targets that correlates precisely to the position of its ganglion cell body in the retina relative to its neighbouring cells. In this way, axons originating in the most nasal retina project to the most posterior areas in the targets, whereas those originating more temporally terminate progressively more anteriorly (Figure 4). In addition, axons from the dorsal retina innervate the lateral targets, and axons from the ventral retina innervate the medial targets. Thus, the entire retinal image is mapped point-to-point on to the targets. This form of organisation, termed topographical mapping, is the most parsimonious way of transferring spatially structured information from one group of neurons to the next. See also: Topographic Maps in the Brain To establish a specific and accurate topographical map, mechanisms must exist to provide each axon with positional information relative to its neighbours. Roger Sperry first proposed the presence of ‘cytochemical tags’ after his classical experiments in the 1940s. Sperry detached and rotated frog’s eyes by 1808, and analysed the effects on their behaviour. After regeneration, the frogs behaved as though their visual maps had been inverted; leaping backwards for lures presented ahead of them, and diving down for lures presented above them. This suggested to Sperry that a given location in the retina connected to a given location in the tectum. A stimulus presented above the frog will stimulate ventral RGCs. However, after eye inversion, these ventral RGCs bear the ‘cytochemical tag’ of a dorsal RGC, and connect to the brain as a dorsal RGC would. Thus, the frog interprets a stimulus above as a stimulus below and dives in the wrong direction. See also: Sperry, Roger Wolcott The molecular nature of the ‘cytochemical tags’ predicted by Sperry are being unravelled. Gradients of ligands that guide axon growth have been identified in the LGN and the SC, whereas complementary gradients of receptors for these ligands are expressed by RGC axons (Figure 4). In particular, Ephrin-A ligands of the highly conserved EphA family of receptor tyrosine kinases exist in the visual targets. In the SC ephrin-A expression is highest in the posterior areas and progressively decreases more anteriorly. In the retina, EphA receptors are more highly expressed in the most temporal retina and decrease towards the nasal retina. Ephrin-A ligands induce a concentration-dependent response by RGC axons, such that axon growth is inhibited by higher concentrations of ligand, but axon growth is supported at lower concentrations. Axon responses thus depend on RGC position in the retina, given the gradients of receptor expression. Thus, temporal axons that innervate the anterior colliculus express more receptor and require less ligand to cause termination in the target tissue. Axons originating more nasally in the retina express fewer receptors, and therefore require a higher level of ligand to cause termination. Consequently, more nasal axons grow through to the posterior SC where there are higher ligand concentrations, whereas temporal axons are kept out of the posterior SC by an increasing gradient of repulsive molecules. Similar rules apply to the LGN. eLS & 2013, John Wiley & Sons, Ltd. www.els.net 7 Visual System Development in Vertebrates EphA Dorsal Temporal EphB Nasal Ventral Anterior Medial Lateral Posterior EphrinA EphrinB Figure 4 Topographical mapping of retinal axons on to the SC. The retinocollicular connection is highly organised, such that axons from the neighbouring neurons in the retina terminate in neighbouring positions in the SC. Axons originating in the nasal retina terminate in the caudal SC, whereas temporal RGCs send axons to the rostral colliculus. In addition, axons originating in the dorsal retina map to the lateral SC, whereas ventral RGC axons terminate in the medial SC. Retinocollicular mapping is mediated by reciprocal molecular gradients in the retina and SC. EphA receptors are expressed by RGCs in an increasing nasal-temporal gradient. Nasal neurons express few EphA receptors, whereas neurons located more temporally express progressively more receptors. Ephrin-A ligands, which inhibit RGC elongation, are expressed in the SC in an increasing anterior–posterior gradient. Nasal RGC axons project further into the SC because they express fewer EphA receptors and are subsequently less sensitive to the repulsive Ephrin-A ligands. Conversely, the axons of temporal RGCs invade only a short distance into the SC because of their high sensitivity to Ephrin-A ligands. In the dorsoventral axis, a gradient of EphB receptors exists in the retina with highest expression ventrally, while a gradient of Ephrin-B, highest medially, is expressed in the colliculus. In this case, however, EphB/ephrin-B signalling seems to mediate attraction. The reciprocal expression of ligands and receptors in the retina and colliculus also contributes to topographical mapping in the dorsal–ventral axis, but in this case pathfinding is regulated by graded attraction of retinal axons. In frogs, EphB1-expressing cells in the ventral tectum appear to attract Ephrin-B expressing axons from the dorsal retina. In mice EphB-expressing axons from the ventral retina project to medial collicular areas that express high levels of Ephrin-B1 ligands. In cooperation with the molecular organisation underlying the anterior–posterior axon targeting, this three-dimensional spatiotemporal regulation of Eph/ephrin, together with other guidance 8 molecules, provides an extremely accurate mechanism for the topographic mapping of RGC axons to their target tissues in the brain. See also: Ephrins The graded expression of EphAs and EphBs along the T– N and D–V retinal axis required for topographic mapping results from the early events that determine retinal polarity. For instance, the expression of the transcription factors Foxg1 and Foxd1 along the T–N axis early in the development is essential for the later gradual expression of retinal EphA/ephrinAs. Similarly, early expression of Vax2 or Tbx5 is critical for determining a correct EphB/ephrin-Bs retinal gradient (McLaughlin et al., 2003a). eLS & 2013, John Wiley & Sons, Ltd. www.els.net Visual System Development in Vertebrates Further refinement of the retinotopic map before eye opening is thought to require spontaneous electrical activity within the RGCs themselves. RGCs in the developing retina, even before the formation of functional photoreceptors, exhibit spontaneous activity. This activity, in the form of retinal waves, are spontaneous bursts of action potentials that originate in one specific subtype of amacrine cells, the starburst amacrine cells, and propagate in a wave-like fashion across the RGC layer, such that the neighbouring RGCs fire nearly synchronously. Genetic or Retina Optic chiasm LGN Primary visual cortex (a) Ocular dominance columns Blobs C Layers I 1 2 3 C I 4A 4B 4C 4C 5 6 Orientation columns (c) 5I 3I 6C 2I 4C From 1C 3I 4C 5I 6C 2I LGN 1C (b) Figure 5 Diagram of the retinogeniculocortical projection in primates. (a) An outline of the pathway, going from the retina (top) through the optic chiasm to the lateral geniculate nucleus (LGN). Second relay neurons in the LGN project to layer 4 of the primary visual cortex, maintaining a rough topographical map of the visual world. (b) Projections from the retina to the LGN. Retinal ganglion cells project to eye-specific layers within the LGN. Axons from the nasal half of the contralateral eye (C) project to layers 1C, 4C and 6C, whereas temporal axons from the ipsilateral eye project to layers 2I, 3I and 5I. (c) Structure of hypercolumns in the primary visual cortex. LGN inputs arrive in layer 4, where they are segregated into ocular dominance columns, blobs and orientation-selective columns. Adapted from Kandel et al. (1991). & McGraw-Hill. eLS & 2013, John Wiley & Sons, Ltd. www.els.net 9 Visual System Development in Vertebrates pharmacological blockage of retinal waves produces a poorly defined retinotopic map at the targets (McLaughlin et al., 2003b; Huberman et al., 2008). See also: Neural Activity and the Development of Brain Circuits Eye-specific layering of retinal axons at the visual targets In addition to receiving retinal input in a topographic manner, the main visual targets are innervated in an eyespecific fashion in mammals. The LGN and SC are formed by layers that receive input from each eye (see Figure 5a). The right targets receive input from the nasal half of the left retina and the temporal half of the right retina, whereas the left targets receive input from the nasal half of the right retina and temporal half of the left retina. Each layer of the mature targets contains positionally mapped input from one eye, such that the adjacent layers receive input from opposite eyes. RGCs responsive to topographically identical coordinates in the visual field project to precisely the same location in the LGN, but in different eye-specific layers (Figure 5). See also: Brain Imaging: Localization of Brain Functions This layer specificity is not established from the beginning. Early in development ganglion cell axons from each eye intermingle, with separation mediated by activitydependent mechanisms. Inhibition of retinal waves prevents the formation of eye-specific layers in the targets. Similarly, if one eye is removed early in development, axons from the remaining eye will invade the layer corresponding to the other eye. Thus, patterned activity occurring independently in each eye drives the layer-specific segregation of axons via a competitive mechanism (Huberman, 2007). Ipsilateral but not contralateral axons express the serotonin transporter (Sert) in a Zic2-dependent manner. In the absence of Sert eye-specific refinement is perturbed, resembling the phenotype observed when retinal waves are blocked (Garcia-Frigola and Herrera, 2010). It is unclear, however, whether and how the serotonin pathway interacts with spontaneous activity to shape eye-specific layering. See also: Neural Activity and the Development of Brain Circuits The primary visual cortex: the main visual processing centre The second relay neurons in the LGN that receive synaptic input from the retina send their axons to layer 4 of the ipsilateral primary visual cortex, maintaining a rough topographical map (Figure 5). Thalamocortical topography is also established by guidance molecules such as EphrinAs that are expressed in a rostral-low to caudal-high gradient within the ventral telencephalon and EphA receptors that are expressed in a complementary gradient within the dorsal thalamus, rostromedial-high to caudolateral-low. Interactions between ephrin-A ligands and EphA receptors are essential to establish the initial topographic 10 arrangement of thalamocortical connections as the axons enter the ventral telencephalon. In addition to being topographically arranged in the visual cortex, LGN inputs are segregated into right and left eye-specific patches as a consequence of activity-dependent competition between the axons representing each eye. Similar to the development of connections in the LGN, establishment of these ocular dominance columns depends on differential temporal patterns of retinal activity. Blocking neural activity, or synchronous stimulation of retinal ganglion cells in both eyes, disrupts the formation of ocular dominance columns. Information in the visual cortex is also segregated according to stimulus orientation. Orientation columns are organised cortical regions perpendicular to the cortex containing neurons that respond to a stimulus oriented at the same angle. Initially, orientation columns form as a low-contrast map, where sensitivity to different orientations is not clearly segregated. However, before ocular dominance column formation, these orientation columns become exquisitely tuned, so the neighbouring locations in the cortex are sensitive to similar angles of stimulus orientation. Unlike ocular dominance columns, however, orientation-selective columns develop normally in the absence of visual stimulation. Orientation column formation can be blocked by inhibiting activity in the visual cortex, suggesting that interactions within the cortex help to establish these columns (White and Fitzpatrick, 2007). As development proceeds, the visual cortex further refines the segregation of visual information into its component parts, resulting in a repeating pattern of complex functional units called hypercolumns (Figure 5). Hypercolumns contain not only orientation-selective columns and ocular dominance columns, but also a third system of columns called blobs, which receive information on object colour. These functional subunits are refined via activitydependent mechanisms. Within the primary visual cortex, a visual object is separated into information regarding its shape, movement and colour. The formation of synaptic connections between neurons in different layers within the primary visual cortex, as well as connections between different visual cortical areas, is likely to help reassemble a visual image, for we do not see simply patterns of shapes and colours, but rather an intact representation of the visual world. See also: Cerebral Cortex Development References Brittis PA, Canning DR and Silver J (1992) Chondroitin sulfate as a regulator of neuronal patterning in the retina. Science 255: 733–736. Chiang C, Litingtung Y, Lee E et al. (1996) Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 383: 407–413. Deiner MS, Kennedy TE, Fazeli A et al. (1997) Netrin-1 and DCC mediate axons guidance locally at the optic disc: loss of function leads to optic nerve hypoplasia. Neuron 19: 575–589. eLS & 2013, John Wiley & Sons, Ltd. www.els.net Visual System Development in Vertebrates Dowling JE (1970) Organization of vertebrate retimes. Investigative Ophthalmology 9: 655–680. Erskine L, Reijntjes S, Pratt T et al. (2011) VEGF-signaling through neuropilin 1 guides commissural axon crossing at the optic chiasm. Neuron 70: 951–965. Fricke C, Lee JS, Geiger-Rudolph S, Bonhoeffer F and Chien CB (2001) astray, a zebrafish roundabout homolog required for retinal axon guidance. Science 292: 507–510. Fuerst PG, Bruce F, Tian M et al. (2009) DSCAM and DSCAML1 function in self-avoidance in multiple cell types in the developing mouse retina. Neuron 64: 484–497. Fuerst PG, Koizumi A, Masland RH and Burgess RW (2008) Neurite arborization and mosaic spacing in the mouse retina require DSCAM. Nature 451: 470–474. Garcia-Frigola C, Carreres MI, Vegar C, Mason C and Herrera E (2008) Zic2 promotes axonal divergence at the optic chiasm midline by EphB1-dependent and -independent mechanisms. Development 135: 1833–1844. Garcia-Frigola C and Herrera E (2010) Zic2 regulates the expression of Sert to modulate eye-specific refinement at the visual targets. EMBO Journal 29: 3170–3183. Herrera E, Brown L, Aruga J et al. (2003) Zic2 patterns binocular vision by specifying the uncrossed retinal projection. Cell 114: 545–557. Höpker VH, Shewan D, Tessier-Lavigne M, Poo M and Holt C (1999) Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1. Nature 401: 69–73. Huberman AD (2007) Mechanisms of eye-specific visual circuit development. Current Opinion in Neurobiology 17: 73–80. Huberman AD, Feller MB and Chapman B (2008) Mechanisms underlying development of visual maps and receptive fields. Annual Review of Neuroscience 31: 379–509. Kandel ER, Schwartz JH and Jessell TM (1991) Principles of Neural Science, 3rd edn. East Norwalk, CT: Appleton and Lange. Kolpak A, Zhang J and Bao ZZ (2005) Sonic hedgehog has a dual effect on the growth of retinal ganglion cell axons depending on its concentration. Journal of Neuroscience 25: 3432–3441. Kuwajima T, Yoshida Y, Takegahara N et al. (2012) Optic chiasm presentation of Sepmaphorin6D in the context of Plexin-A1 and Nr-CAM promotes retinal axon midline crossing. Neuron 74: 676–690. Matsuoka RL, Chivatakarn O, Badea TC et al. (2011b) Class 5 transmembrane semaphorins control selective mammalian retinal lamination and function. Neuron 71: 460–473. Matsuoka RL, Nguyen-Ba-Charvet KT, Parray A et al. (2011a) Transmembrane semaphorin signalling controls laminar stratification in the mammalian retina. Nature 470: 259–263. McLaughlin T, Hindges R and O’Leary DD (2003a) Regulation of axial patterning of the retina and its topographic mapping in the brain. Current Opinion in Neurobiology 13: 57–69. McLaughlin T, Torborg CL, Feller MB and O’Leary DD (2003b) Retinotopic map refinement requires spontaneous retinal waves during a brief critical period of development. Neuron 40: 1147–1160. Müller F, Albert S, Blader P et al. (2000) Direct action of a nodal-related signal cyclops in induction of sonic hedgehog in the ventral midline of the CNS. Development 127: 3889–3897. Nakagawa S, Brennan C, Johnson KG et al. (2000) Ephrin-B regulates the ipsilateral routing of retinal axons at the optic chiasm. Neuron 25: 599–610. Plump AS, Erskine L, Sabatier C et al. (2002) Slit1 and Slit2 cooperate to prevent premature midline crossing of retinal axons in the mouse visual system. Neuron 17: 219–232. Sakai JA and Halloran MC (2006) Seamaphorin 3d guides laterality of retinal ganglion cell projections in zebrafish. Development 133: 1035–1044. Thompson H, Camand O, Barker D and Erskine L (2006) Slit proteins regulate distinct aspects of retinal ganglion cell axon guidance within dorsal and ventral retina. Journal of Neuroscience 26: 8082–8091. White LE and Fitzpatrick D (2007) Vision and cortical map development. Neuron 56: 327–338. Williams SE, Mann F, Erskine L et al. (2003) Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm. Neuron 39: 919–935. Yamagata M and Sanes JR (2008) Dscam and Sidekick proteins direct lamina-specific synaptic connections in vertebrate retina. Nature 451: 465–469. Further Reading Adler R and Canto-Soler MV (2007) Molecular mechanisms of optic vesicle development: complexities, ambiguities and controversies. Developmental Biology 305: 1–13. Donner AL, Lachke SA and Maas RL (2006) Lens induction in vertebrates: variations on a conserved theme of signaling events. Seminars in Cell and Developmental Biology 17: 676–685. Erskine L and Herrera E (2007) The retinal ganglion cell axon’s journey: insights into molecular mechanisms of axon guidance. Developmental Biology 308: 1–14. Gilbert SF (2010) Developmental Biology, 9th edn, Sunderland, MA, USA: Sinauer Associates Inc. Harada T, Harada C and Parada LF (2007) Molecular regulation of visual system development: more than meets the eye. Genes and Development 21: 367–378. Kandel ER, Schwartz JH, Jessell TM, Siegelbaum SA and Hudspeth AJ (2012) Principles of Neural Science, 5th edn, New York, USA: McGraw-Hill Medical. Petros TJ, Rebsam A and Mason CA (2008) Retinal axon growth at the optic chiasm: to cross or not to cross. Annual Review of Neuroscience 31: 295–315. Price D, Jarman AP, Mason JO and Kind PC (2011) Building Brains: An Introduction to Neural Development, 1st edn. Chichester, West Susses, UK: Wiley-Blackwell. eLS & 2013, John Wiley & Sons, Ltd. www.els.net 11