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The eye is a peripheral outpost of the central nervous system (CNS) where the retinal ganglion cells (RGCs) reside. RGC axons navigate to their targets in a remarkably stereotyped and error-free manner and it is this process of directed growth that underlies the complex organization of the adult brain. The RGCs are the only retinal neurons to project into the brain and their peripheral location makes them an unusually accessible population of projection neurons for experiments involving in vivo gene transfer, anatomical tracing, transplantation and in vitro culture. In this paper, we review recent findings that have contributed to our understanding of some of the guidance decisions that axons make in the developing visual system. We look at two choice points in the pathway, the optic nervehead (onh) and the midline chiasm, and discuss evidence that supports the idea that key molecules in guiding axon growth at these junctures are netrin-1 (onh) and ephrin-B (chiasm). In the optic tectum where RGCaxon terminals are arrayed in topographic order, we present experimental evidence to suggest that in the dorso-ventral dimension, the B-type ephrins and Eph receptors are of prime importance, possibly through attractive interactions. This complements the anterior-posterior topographic mapping known to be mediated through A-type ephrin/Eph repulsive interactions. An emerging theme is that guidance molecules such as ephrin-B and netrin-1 have complex patterns of restricted expression in the pathway and play multiple and changing roles in axon guidance.
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???displayArticle.pmcLink???PMC3683942 ???displayArticle.link???Int J Dev Biol ???displayArticle.grants???[+]
Fig. 1. Netrin-1 helps to guide the growth of axons out of the eye. (A)
The arrangement of retinal ganglion cells (RGCs; red) along the vitreal
surface of the retina (grey) where laminin is located. Axons grow across
the vitreal surface and make a sharp bend at the entrance to the optic
nerve head (ONH, dark blue; arrow at B) where netrin-1 is localized. (B)
A growth cone entering the ONH where it encounters laminin and netrin-
1 on the vitreal surface and netrin-1 only in the ONH. It is hypothesised
that the laminin and netrin-1 signals combine to repel axons away from
the surface and force axons into the netrin-1-rich ONH, and so out of the
eye.
Fig. 2. Ephrin-B mediates divergent axon choice at the optic chiasm. (A)
Shows the distribution of ephrin-B and EphB receptor in the embryonic retina
(left two panels) and the chiasm of pre- and post- and metamorphic Xenopus
(right two panels). Ephrin-B is expressed in a high-dorsal to low-ventral
gradient in the retina while the EphB receptor is expressed in an opposing
high-ventral to low-dorsal gradient. Ephrin-B is not expressed at the chiasm
until metamorphosis which coincides with the initiation of the ipsilateral
projection. A subpopulation of ventral EphB-expressing cells project ipsilaterally
at metamorphosis. Photomicrographs adapted from Nakagawa et al., 2000
and Mann et al., 2002. (B) Model of repulsive axon guidance at the chiasm.
See text for details. Diagram adapted from Mann and Holt, 2001.
Fig. 3. Topographic mapping along the dorso-ventral axis involves
attractive ephrin/EphB interactions. (A) The normal distribution of Btype
ephrins and receptors in the retina and tectum. Regions of high
ephrin-B expression (dorsal retina) project to regions of high receptor
expression (ventral tectum) indicative of matching, attractive interactions.
(B) Inhibition of EphB receptor function in dorsal retina causes axons to
map significantly further dorsally (like ventral cells) and ectopic expression
of EphB in ventral RGCs causes them to map ventrally (like dorsal cells)
instead of dorsally. Summary of data from Mann et al., 2002.
Fig. 4. Summary of distribution and role of netrin-1, A- and B-type
ephrins and receptors in the developing visual pathway. Eye:
dorsoventral axis is top to bottom, nasotemporal axis left to right.
Tectum: mediolateral (mammals) and dorsoventral (frogs) is top to
bottom, anterior-posterior axis is left to right.
Anderson,
Expression of UNC-5 in the developing Xenopus visual system.
2002, Pubmed,
Xenbase
Anderson,
Expression of UNC-5 in the developing Xenopus visual system.
2002,
Pubmed
,
Xenbase
Birgbauer,
Retinal axon growth cones respond to EphB extracellular domains as inhibitory axon guidance cues.
2001,
Pubmed
Birgbauer,
Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina.
2000,
Pubmed
Braisted,
Graded and lamina-specific distributions of ligands of EphB receptor tyrosine kinases in the developing retinotectal system.
1997,
Pubmed
Brennan,
Two Eph receptor tyrosine kinase ligands control axon growth and may be involved in the creation of the retinotectal map in the zebrafish.
1997,
Pubmed
Brittis,
Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target.
2002,
Pubmed
Campbell,
Chemotropic responses of retinal growth cones mediated by rapid local protein synthesis and degradation.
2001,
Pubmed
,
Xenbase
Ciossek,
Cloning, characterization, and differential expression of MDK2 and MDK5, two novel receptor tyrosine kinases of the eck/eph family.
1995,
Pubmed
Connor,
Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system.
1998,
Pubmed
Corset,
Netrin-1-mediated axon outgrowth and cAMP production requires interaction with adenosine A2b receptor.
2000,
Pubmed
Davis,
Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity.
1994,
Pubmed
Deiner,
Altered midline axon pathways and ectopic neurons in the developing hypothalamus of netrin-1- and DCC-deficient mice.
1999,
Pubmed
Deiner,
Netrin-1 and DCC mediate axon guidance locally at the optic disc: loss of function leads to optic nerve hypoplasia.
1997,
Pubmed
Drescher,
The Eph family in retinal axon guidance.
1997,
Pubmed
Fricke,
astray, a zebrafish roundabout homolog required for retinal axon guidance.
2001,
Pubmed
Hattori,
Regulated cleavage of a contact-mediated axon repellent.
2000,
Pubmed
Herrera,
Zic2 patterns binocular vision by specifying the uncrossed retinal projection.
2003,
Pubmed
Hindges,
EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping.
2002,
Pubmed
Holash,
Reciprocal expression of the Eph receptor Cek5 and its ligand(s) in the early retina.
1997,
Pubmed
Holmberg,
Regulation of repulsion versus adhesion by different splice forms of an Eph receptor.
2000,
Pubmed
Hong,
A ligand-gated association between cytoplasmic domains of UNC5 and DCC family receptors converts netrin-induced growth cone attraction to repulsion.
1999,
Pubmed
,
Xenbase
Hutson,
Pathfinding and error correction by retinal axons: the role of astray/robo2.
2002,
Pubmed
Höpker,
Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1.
1999,
Pubmed
,
Xenbase
Kennedy,
Netrins are diffusible chemotropic factors for commissural axons in the embryonic spinal cord.
1994,
Pubmed
Kullander,
Mechanisms and functions of Eph and ephrin signalling.
2002,
Pubmed
Lauderdale,
Axon tracts correlate with netrin-1a expression in the zebrafish embryo.
1997,
Pubmed
Mann,
Topographic mapping in dorsoventral axis of the Xenopus retinotectal system depends on signaling through ephrin-B ligands.
2002,
Pubmed
,
Xenbase
Mann,
B-type Eph receptors and ephrins induce growth cone collapse through distinct intracellular pathways.
2003,
Pubmed
,
Xenbase
Marcus,
Eph family receptors and their ligands distribute in opposing gradients in the developing mouse retina.
1996,
Pubmed
Marston,
Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion.
2003,
Pubmed
Mason,
Glia, neurons, and axon pathfinding during optic chiasm development.
1997,
Pubmed
McLaughlin,
Regulation of axial patterning of the retina and its topographic mapping in the brain.
2003,
Pubmed
McLaughlin,
Bifunctional action of ephrin-B1 as a repellent and attractant to control bidirectional branch extension in dorsal-ventral retinotopic mapping.
2003,
Pubmed
Ming,
cAMP-dependent growth cone guidance by netrin-1.
1997,
Pubmed
,
Xenbase
Nakagawa,
Ephrin-B regulates the Ipsilateral routing of retinal axons at the optic chiasm.
2000,
Pubmed
,
Xenbase
Sefton,
Novel expression gradients of Eph-like receptor tyrosine kinases in the developing chick retina.
1997,
Pubmed
Serafini,
The netrins define a family of axon outgrowth-promoting proteins homologous to C. elegans UNC-6.
1994,
Pubmed
Shewan,
Age-related changes underlie switch in netrin-1 responsiveness as growth cones advance along visual pathway.
2002,
Pubmed
,
Xenbase
Shirasaki,
Guidance of circumferentially growing axons by netrin-dependent and -independent floor plate chemotropism in the vertebrate brain.
1996,
Pubmed
Song,
Signal transduction underlying growth cone guidance by diffusible factors.
1999,
Pubmed
Stein,
Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses.
1998,
Pubmed
Strähle,
Expression and regulation of a netrin homologue in the zebrafish embryo.
1997,
Pubmed
Stuermer,
The retinal axon's pathfinding to the optic disk.
2000,
Pubmed
Vidovic,
Marsupial retinocollicular system shows differential expression of messenger RNA encoding EphA receptors and their ligands during development.
1999,
Pubmed
Vidovic,
Analysis of EphB receptors and their ligands in the developing retinocollicular system of the wallaby reveals dynamic patterns of expression in the retina.
2003,
Pubmed
Williams,
Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm.
2003,
Pubmed
,
Xenbase
Zimmer,
EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion.
2003,
Pubmed
de la Torre,
Turning of retinal growth cones in a netrin-1 gradient mediated by the netrin receptor DCC.
1997,
Pubmed
,
Xenbase
