Bifunctional action of ephrin-B1 as a repellent and attractant to control bidirectional branch extension in dorsal-ventral retinotopic mapping

We report that the EphB receptor ligand, ephrin-B1, may act bifunctionally as both a branch repellent and attractant to control the unique mechanisms in mapping the dorsal-ventral (DV) retinal axis along the lateral-medial (LM) axis of the optic tectum. EphB receptors are expressed in a low to high DV gradient by retinal ganglion cells (RGCs), and ephrin-B1 is expressed in a low to high LM gradient in the tectum. RGC axons lack DV ordering along the LM tectal axis, but directionally extend interstitial branches that establish retinotopically ordered arbors. Recent studies show that ephrin-B1 acts as an attractant in DV mapping and in controlling directional branch extension. Modeling indicates that proper DV mapping requires that this attractant activity cooperates with a repellent activity in a gradient that mimics ephrin-B1. We show that ectopic domains of high, graded ephrin-B1 expression created by retroviral transfection repel interstitial branches of RGC axons and redirect their extension along the LM tectal axis, away from their proper termination zones (TZs). In contrast, the primary RGC axons are unaffected and extend through the ectopic domains of ephrin-B1 and arborize at the topographically correct site. However, when the location of a TZ is coincident with ectopic domains of ephrin-B1, the domains appear to inhibit arborization and shape the distribution of arbors. Our findings indicate that ephrin-B1 selectively controls, through either attraction or repulsion, the directional extension and arborization of interstitial branches extended by RGC axons arising from the same DV position: branches that arise from axons positioned lateral to the correct TZ are attracted up the gradient of ephrin-B1 and branches that arise from axons positioned medial to the same TZ are repelled down the ephrin-B1 gradient. Alternatively, EphB receptor signaling may act as a `ligand-density sensor' and titrate signaling pathways that promote branch extension toward an optimal ephrin-B1 concentration found at the TZ; branches located either medial or lateral to the TZ would encounter a gradient of increasingly favored attachment in the direction of the TZ.

[1]  D. O'Leary,et al.  Graded and lamina-specific distributions of ligands of EphB receptor tyrosine kinases in the developing retinotectal system. , 1997, Developmental biology.

[2]  A. Lane,et al.  Surface densities of ephrin‐B1 determine EphB1‐coupled activation of cell attachment through αvβ3 and α5β1 integrins , 1999 .

[3]  Mu-ming Poo,et al.  Signal transduction underlying growth cone guidance by diffusible factors , 1999, Current Opinion in Neurobiology.

[4]  M. Poo,et al.  Expression of a Putative Vesicular Acetylcholine Transporter Facilitates Quantal Transmitter Packaging , 1997, Neuron.

[5]  J. Flanagan,et al.  Axonal Protein Synthesis Provides a Mechanism for Localized Regulation at an Intermediate Target , 2002, Cell.

[6]  Dennis D.M. O'Leary,et al.  Responses of retinal axons in vivo and in vitro to position-encoding molecules in the embryonic superior colliculus , 1992, Neuron.

[7]  Chad A. Cowan,et al.  Kinase independent function of EphB receptors in retinal axon pathfinding to the optic disc from dorsal but not ventral retina. , 2000, Development.

[8]  D. O'Leary,et al.  Control of topographic retinal axon branching by inhibitory membrane-bound molecules. , 1994, Science.

[9]  C. Cepko,et al.  Replication-competent retroviral vectors encoding alkaline phosphatase reveal spatial restriction of viral gene expression/transduction in the chick embryo , 1993, Molecular and cellular biology.

[10]  S. Strittmatter,et al.  Semaphorin-mediated axonal guidance via Rho-related G proteins. , 2001, Current opinion in cell biology.

[11]  Mu-ming Poo,et al.  cAMP-Dependent Growth Cone Guidance by Netrin-1 , 1997, Neuron.

[12]  V. Hamburger,et al.  A series of normal stages in the development of the chick embryo. 1951. , 2012, Developmental dynamics : an official publication of the American Association of Anatomists.

[13]  G. Rougon,et al.  Control of semaphorin signaling , 2002, Current Opinion in Neurobiology.

[14]  D. O'Leary,et al.  A POU Domain Transcription Factor–Dependent Program Regulates Axon Pathfinding in the Vertebrate Visual System , 2000, Neuron.

[15]  T. Pawson,et al.  Nuk Controls Pathfinding of Commissural Axons in the Mammalian Central Nervous System , 1996, Cell.

[16]  E. Pasquale,et al.  Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system. , 1998, Developmental biology.

[17]  John G Flanagan,et al.  Topographic Guidance Labels in a Sensory Projection to the Forebrain , 1998, Neuron.

[18]  D. O'Leary,et al.  Neurotrophins Rapidly Modulate Growth Cone Response to the Axon Guidance Molecule, Collapsin-1 , 1998, Molecular and Cellular Neuroscience.

[19]  D. O'Leary,et al.  EphB Forward Signaling Controls Directional Branch Extension and Arborization Required for Dorsal-Ventral Retinotopic Mapping , 2002, Neuron.

[20]  John G. Flanagan,et al.  Genetic Analysis of Ephrin-A2 and Ephrin-A5 Shows Their Requirement in Multiple Aspects of Retinocollicular Mapping , 2000, Neuron.

[21]  C. Holt,et al.  Chemotropic Responses of Retinal Growth Cones Mediated by Rapid Local Protein Synthesis and Degradation , 2001, Neuron.

[22]  D. O'Leary,et al.  Dynamics of target recognition by interstitial axon branching along developing cortical axons , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[23]  Mu-ming Poo,et al.  A Ligand-Gated Association between Cytoplasmic Domains of UNC5 and DCC Family Receptors Converts Netrin-Induced Growth Cone Attraction to Repulsion , 1999, Cell.

[24]  J R Sanes,et al.  Lamina-specific connectivity in the brain: regulation by N-cadherin, neurotrophins, and glycoconjugates. , 1997, Science.

[25]  Paul A Yates,et al.  Topographic Mapping from the Retina to the Midbrain Is Controlled by Relative but Not Absolute Levels of EphA Receptor Signaling , 2000, Cell.

[26]  Scott E. Fraser,et al.  Effects of brain-derived neurotrophic factor on optic axon branching and remodelling in vivo , 1995, Nature.

[27]  Jürgen Löschinger,et al.  In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases , 1995, Cell.

[28]  S. Henke-Fahle,et al.  Avoidance of posterior tectal membranes by temporal retinal axons. , 1987, Development.

[29]  C. Holt,et al.  Topographic Mapping in Dorsoventral Axis of the Xenopus Retinotectal System Depends on Signaling through Ephrin-B Ligands , 2002, Neuron.

[30]  D. O'Leary,et al.  Inaccuracies in initial growth and arborization of chick retinotectal axons followed by course corrections and axon remodeling to develop topographic order , 1989, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[31]  F. Bonhoeffer,et al.  In vitro experiments on axon guidance demonstrating an anterior‐posterior gradient on the tectum. , 1982, The EMBO journal.

[32]  D. O'Leary,et al.  The homeodomain protein Vax2 patterns the dorsoventral and nasotemporal axes of the eye. , 2002, Development.

[33]  J. Frisén,et al.  Regulation of repulsion versus adhesion by different splice forms of an Eph receptor , 2000, Nature.

[34]  Alfred Gierer,et al.  Directional cues for growing axons forming the retinotectal projection , 1987 .

[35]  T. McLaughlin,et al.  Topographic-Specific Axon Branching Controlled by Ephrin-As Is the Critical Event in Retinotectal Map Development , 2001, The Journal of Neuroscience.

[36]  D. O'Leary,et al.  Regulation of axial patterning of the retina and its topographic mapping in the brain , 2003, Current Opinion in Neurobiology.

[37]  John G Flanagan,et al.  Topographically Specific Effects of ELF-1 on Retinal Axon Guidance In Vitro and Retinal Axon Mapping In Vivo , 1996, Cell.

[38]  E. Pasquale,et al.  Polarized expression of the receptor protein tyrosine kinase Cek5 in the developing avian visual system. , 1995, Developmental biology.

[39]  David J. Anderson,et al.  Eph Family Transmembrane Ligands Can Mediate Repulsive Guidance of Trunk Neural Crest Migration and Motor Axon Outgrowth , 1997, Neuron.

[40]  M. Bastmeyer,et al.  Collateral branch formation related to cellular structures in the axon tract during corticopontine target recognition , 1998, The Journal of comparative neurology.

[41]  M. Tessier-Lavigne,et al.  The axonal chemoattractant netrin-1 is also a chemorepellent for trochlear motor axons , 1995, Cell.

[42]  Jürgen Löschinger,et al.  Shared and distinct functions of RAGS and ELF‐1 in guiding retinal axons , 1997, The EMBO journal.

[43]  D. O'Leary,et al.  Influence of position along the medial-lateral axis of the superior colliculus on the topographic targeting and survival of retinal axons. , 1992, Brain research. Developmental brain research.

[44]  A. Lane,et al.  Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. , 1998, Genes & development.

[45]  A. Lane,et al.  Surface densities of ephrin-B1 determine EphB1-coupled activation of cell attachment through alphavbeta3 and alpha5beta1 integrins. , 1999, The EMBO journal.

[46]  R. Sperry.  CHEMOAFFINITY IN THE ORDERLY GROWTH OF NERVE FIBER PATTERNS AND CONNECTIONS. , 1963, Proceedings of the National Academy of Sciences of the United States of America.

[47]  D. O'Leary,et al.  Development of topographic order in the mammalian retinocollicular projection , 1992, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[48]  Mu-ming Poo,et al.  Growth-cone attraction to netrin-1 is converted to repulsion by laminin-1 , 1999, Nature.

[49]  Viktor Hamburger,et al.  A series of normal stages in the development of the chick embryo , 1992, Journal of morphology.

[50]  C. Erickson,et al.  Ephrin-B ligands play a dual role in the control of neural crest cell migration. , 2002, Development.

[51]  I. Dawid,et al.  Expression pattern of the murine LIM class homeobox gene Lhx3 in subsets of neural and neuroendocrine tissues , 1995, Developmental dynamics : an official publication of the American Association of Anatomists.