Eph Receptors and Ephrin Ligands in Axon Guidance

  • Michael Reber
  • Robert Hindges
  • Greg Lemke
Part of the Advances in Experimental Medicine and Biology book series (AEMB, volume 621)


The Eph tyrosine kinase receptors (a receptor family named for the expression of Eph in an erythropoietin-producing human hepatocellular carcinoma cell line) make up the largest family of receptor tyrosine kinases. In vertebrates, 14 Eph receptor members have been identified, divided in two sub-groups, the EphAs (EphA1 to A8) and EphBs (EphB1 to B6). Their nine membrane-bound ligands, the ephrins, are also subdivided into the ephrin-As (ephrin-A1 to A6) and ephrin-Bs (ephrin-B1 to B3). The first Eph receptor (EphA1) was identified in 1987, whereas the ephrin ligands were cloned in the mid-90s 1. Eph receptors and ephrins have been found in all animal species analyzed so far, from C. elegans to humans, and are highly conserved through evolution 2. Ephs and ephrins are involved in numerous developmental processes, such as boundary formation, angiogenesis and cell migration. Within the nervous system, Eph signaling regulates the migration pattern of neural crest cells, the boundary formation between hindbrain segments (rhombomeres), the proper formation of the corticospinal tract, the establishment of neural topographic maps and the formation and functional properties of neuronal synapses 1, 3, 4, 5, 6. It is therefore not surprising that nature built a complicated and detailed network of proteins interacting with each other to fine tune each of these important processes. The identity of the receptor or ligand molecule is as important as the structure of the receptor-ligand complex to activate a specific signaling pathway and ultimately elicit the right cell decision.


Growth Cone Dendritic Spine Axon Growth Axon Guidance Nipah Virus 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


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  1. 1.
    Flanagan JG, Vanderhaeghen P. The ephrins and Eph receptors in neural development. Annu Rev Neurosci 1998; 21:309–345.PubMedGoogle Scholar
  2. 2.
    Drescher U. Eph family functions from an evolutionary perspective. Curr Opin Genet Dev 2002; 12:397–402.PubMedGoogle Scholar
  3. 3.
    Dodelet VC, Pasquale EB. Eph receptors and ephrin ligands: Embryogenesis to tumorigenesis. Oncogene 2000; 19:5614–5619.PubMedGoogle Scholar
  4. 4.
    Kullander K, Klein R. Mechanisms and functions of Eph and ephrin signalling. Nat Rev Mol Cell Biol 2002; 3:475–486.PubMedGoogle Scholar
  5. 5.
    Lemke G, Reber M. Retinotectal mapping: New insights from molecular genetics. Annu Rev Cell Dev Biol 2005; 21:551–580.PubMedGoogle Scholar
  6. 6.
    McLaughlin T, O’Leary DD. Molecular gradients and development of retinotopic maps. Annu Rev Neurosci 2005; 28:327–355.PubMedGoogle Scholar
  7. 7.
    Gale NW, Holland SJ, Valenzuela DM et al. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron 1996; 17:9–19.PubMedGoogle Scholar
  8. 8.
    Himanen JP, Chumley MJ, Lackmann M et al. Repelling class discrimination: Ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 2004; 7:501–509.PubMedGoogle Scholar
  9. 9.
    Murai KK, Pasquale EB. ‘Eph’ective signaling: Forward, reverse and crosstalk. J Cell Sci 2003; 116:2823–2832.PubMedGoogle Scholar
  10. 10.
    Koolpe M, Dail M, Pasquale EB. An ephrin mimetic peptide that selectively targets the EphA2 receptor. J. Biol Chem 2002; 277:46974–46979.PubMedGoogle Scholar
  11. 11.
    Himanen JP, Nikolov DB. Eph signaling: A structural view. Trends Neurosci 2003; 26:46–51.PubMedGoogle Scholar
  12. 12.
    Himanen JP, Nikolov DB. Eph receptors and ephrins. Int J Biochem Cell Biol 2003; 35:130–134.PubMedGoogle Scholar
  13. 13.
    Day B, To C, Himanen JP et al. Three distinct molecular surfaces in ephrin-A5 are essential for a functional interaction with EphA3. J Biol Chem 2005; 280:26526–26532.PubMedGoogle Scholar
  14. 14.
    Egea J, Nissen UV, Dufour A et al. Regulation of EphA 4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function. Neuron 2005; 47:515–528.PubMedGoogle Scholar
  15. 15.
    Dickson BJ. Rho GTPases in growth cone guidance. Curr Opin Neurobiol 2001; 11: 103–110.PubMedGoogle Scholar
  16. 16.
    Yuan XB, Jin M, Xu X et al. Signalling and crosstalk of Rho GTPases in mediating axon guidance. Nat Cell Biol 2003; 5:38–45.PubMedGoogle Scholar
  17. 17.
    Kozma R, Sarner S, Ahmed S et al. Rho family GTPases and neuronal growth cone remodelling: Relationship between increased complexity induced by Cdc42Hs, Rac1, and acetylcholine and collapse induced by RhoA and lysophosphatidic acid. Mol Cell Biol 1997; 17:1201–1211.PubMedGoogle Scholar
  18. 18.
    Shamah SM, Lin MZ, Goldberg JL et al. EphA receptors regulate growth cone dynamics through the novel guanine nucleotide exchange factor ephexin. Cell 2001; 105:233–244.PubMedGoogle Scholar
  19. 19.
    Sahin M, Greer PL, Lin MZ et al. Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 2005; 46:191–204.PubMedGoogle Scholar
  20. 20.
    Cowan CW, Shao YR, Sahin M et al. Vav family GEFs link activated Ephs to endocytosis and axon guidance. Neuron 2005; 46:205–217.PubMedGoogle Scholar
  21. 21.
    Tanaka M, Ohashi R, Nakamura R et al. Tiam1 mediates neurite outgrowth induced by ephrin-B1 and EphA2. EMBO J 2004; 23:1075–1088.PubMedGoogle Scholar
  22. 22.
    Knöll B, Drescher U. Src family kinases are involved in EphA receptor-mediated retinal axon guidance. J Neurosci 2004; 24:6248–6257.PubMedGoogle Scholar
  23. 23.
    Jurney WM, Gallo G, Letourneau PC et al. Rac1-mediated endocytosis during ephrin-A2-and semaphorin 3A-induced growth cone collapse. J Neurosci 2002; 22:6019–6028.PubMedGoogle Scholar
  24. 24.
    Wahl S, Barth H, Ciossek T et al. Ephrin-A5 induces collapse of growth cones by activating Rho and Rho kinase. J Cell Biol 2000; 149:263–270.PubMedGoogle Scholar
  25. 25.
    Noren NK, Pasquale EB. Eph receptor-ephrin bidirectional signals that target Ras and Rho proteins. Cell Signal 2004; 16:655–666.PubMedGoogle Scholar
  26. 26.
    Miao H, Wei BR, Peehl DM et al. Activation of EphA receptor tyrosine kinase inhibits the Ras/ MAPK pathway. Nat Cell Biol 2001; 3:527–530.PubMedGoogle Scholar
  27. 27.
    Marquardt T, Shirasaki R, Ghosh S et al. Coexpressed EphA receptors and ephrin-A ligands mediate opposing actions on growth cone navigation from distinct membrane domains. Cell 2005; 121:127–139.PubMedGoogle Scholar
  28. 28.
    Davy A, Gale NW, Murray EW et al. Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion. Genes Dev 1999; 13:3125–3135.PubMedGoogle Scholar
  29. 29.
    Davy A, Robbins SM. Ephrin-A5 molulates cell adhesion and morphology in an integrin-dependent manner. EMBO J 2000; 19:5396–5405.PubMedGoogle Scholar
  30. 30.
    Huai J, Drescher U. An ephrin-A-dependent signaling pathway controls integrin function and is linked to the tyrosine phosphorylation of a 120-kDa protein. J Biol Chem 2001; 276:6689–6694.PubMedGoogle Scholar
  31. 31.
    Connor RJ, Menzel P, Pasquale EB. Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system. Dev Biol 1998; 193:21–35.PubMedGoogle Scholar
  32. 32.
    Hornberger MR, Dütting D, Ciossek T et al. Modulation of EphA receptor function by coexpressed ephrinA ligands on retinal ganglion cell axons. Neuron 1999; 22:731–742.PubMedGoogle Scholar
  33. 33.
    Yin Y, Yamashita Y, Noda H et al. EphA receptor tyrosine kinases interact with coexpressed ephrin-A ligands in cis. Neurosci Res 2004; 48:285–296.PubMedGoogle Scholar
  34. 34.
    Carvalho RF, Beutler M, Marler KJ et al. Silencing of EphA3 through a cis interaction with ephrinA5. Nat Neurosci 2006; 9:322–330.PubMedGoogle Scholar
  35. 35.
    Hattori M, Osterfield M, Flanagan JG. Regulated cleavage of a contact-mediated axon repellent. Science 2000; 289:1360–1365.PubMedGoogle Scholar
  36. 36.
    Janes PW, Saha N, Barton WA et al. Adam meets Eph: An ADAM substrate recognition module acts as a molecular switch for ephrin cleavage in trans. Cell 2005; 123:291–304.PubMedGoogle Scholar
  37. 37.
    Penzes P, Beeser A, Chernoff J et al. Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 2003; 37:263–274.PubMedGoogle Scholar
  38. 38.
    Irie F, Yamaguchi Y. EphB receptors regulate dendritic spine development via intersectin, Cdc42 and N-WASP. Nat Neurosci 2002; 5:1117–1118.PubMedGoogle Scholar
  39. 39.
    Marai KK, Pasquale EB. Eph receptors, ephrins, and synaptic function. Neuroscientist 2004; 10:304–314.Google Scholar
  40. 40.
    Tong J, Elowe S, Nash P et al. Manipulation of EphB2 regulatory motifs and SH2 binding sites switches MAPK signaling and biological activity. J Biol Chem 2003; 278:6111–6119.PubMedGoogle Scholar
  41. 41.
    Zou JX, Wang B, Kalo MS et al. An Eph receptor regulates integrin activity through R-Ras. Proc Natl Acad Sci USA 1999; 96:13813–13818.PubMedGoogle Scholar
  42. 42.
    Nagashima K, Endo A, Ogita H et al. Adaptor protein Crk is required for ephrin-B1-induced membrane ruffling and focal complex assembly of human aortic endothelial cells. Mol Biol Cell 2002; 13:4231–4242.PubMedGoogle Scholar
  43. 43.
    Stein E, Lane AA, Cerretti DP et al. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev 1998; 12:667–678.PubMedGoogle Scholar
  44. 44.
    Becker E, Huynh-Do U, Holland S et al. Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol Cell Biol 2000; 20:1537–1545.PubMedGoogle Scholar
  45. 45.
    Stein E, Huynh-Do U, Lane AA et al. Nck recruitment to Eph receptor, EphB1/ELK, couples ligand activation to c-jun kinase. J Biol Chem 1998; 273:1303–1308.PubMedGoogle Scholar
  46. 46.
    Holland SJ, Gale NW, Mbamalu G et al. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature 1996; 383:722–725.PubMedGoogle Scholar
  47. 47.
    Brückner K, Pasquale EB, Klein R. Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 1997; 275:1640–1643.PubMedGoogle Scholar
  48. 48.
    Wilkinson DG. Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci 2001; 2:155–164.PubMedGoogle Scholar
  49. 49.
    Cowan CA, Henkemeyer M. The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 2001; 413:174–179.PubMedGoogle Scholar
  50. 50.
    Garrity PA, Rao Y, Salecker I et al. Drosophila photoreceptor axon guidance and targeting requires the dreadlocks SH2/SH3 adapter protein. Cell 1996; 85:639–650.PubMedGoogle Scholar
  51. 51.
    Cowan CA, Henkemeyer M. Ephrins in reverse, park and drive. Trends Cell Biol 2002; 12:339–346.PubMedGoogle Scholar
  52. 52.
    Lu Q, Sun EE, Klein RS et al. Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 2001; 105:69–79.PubMedGoogle Scholar
  53. 53.
    Xu Z, Lai KO, Zhou HM et al. Ephrin-B1 reverse signaling activates JNK through a novel mechanism that is independent of tyrosine phosphorylation. J Biol Chem 2003; 278:24767–24775.PubMedGoogle Scholar
  54. 54.
    Tanaka M, Kamo T, Ota S et al. Association of Dishevelled with Eph tyrosine kinase receptor and ephrin mediates cell repulsion. EMBO J 2003; 22:847–858.PubMedGoogle Scholar
  55. 55.
    Lee HS, Bong YS, Moore KB et al. Dishevelled mediates ephrinB1 signalling in the eye field through the planar cell polarity pathway. Nat Cell Biol 2006; 8:55–63.PubMedGoogle Scholar
  56. 56.
    Zimmer M, Palmer A, Köhler J et al EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat Cell Biol 2003; 5:869–878.PubMedGoogle Scholar
  57. 57.
    Marston DJ, Dickinson S, Nobes CD. Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion. Nat Cell Biol 2003; 5:879–888.PubMedGoogle Scholar
  58. 58.
    Palmer A, Klein R. Multiple roles of ephrins in morphogenesis, neuronal networking, and brain function. Genes Dev 2003; 17:1429–1450.PubMedGoogle Scholar
  59. 59.
    Yamaguchi Y, Pasquale EB. Eph receptors in the adult brain. Curr Opin Neurobiol 2004; 14:288–296.PubMedGoogle Scholar
  60. 60.
    Cooke JE, Moens CB. Boundary formation in the hindbrain: Eph only it were simple. Trends Neurosci 2002; 25:260–267.PubMedGoogle Scholar
  61. 61.
    Mellitzer G, Xu Q, Wilkinson DG. Eph receptors and ephrins restrict cell intermingling and communication. Nature 1999; 400:77–81.PubMedGoogle Scholar
  62. 62.
    Cooke JE, Kemp HA, Moens CB. EphA4 is required for cell adhesion and rhombomere-boundary formation in the zebrafish. Curr Biol 2005; 15:536–542.PubMedGoogle Scholar
  63. 63.
    Cooke J, Moens C, Roth L et al. Eph signalling functions downstream of Val to regulate cell sorting and boundary formation in the caudal hindbrain. Development 2001; 128:571–580.PubMedGoogle Scholar
  64. 64.
    Dottori M, Hartley L, Galea M et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc Natl Acad Sci USA 1998; 95:13248–13253.PubMedGoogle Scholar
  65. 65.
    Kullander K, Croll SD, Zimmer M et al. Ephrin-B3 is the midline barrier that prevents corticospinal tract axons from recrossing, allowing for unilateral motor control. Genes Dev 2001; 15:877–888.PubMedGoogle Scholar
  66. 66.
    Kullander K, Mather NK, Diella F et al. Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 2001; 29:73–84.PubMedGoogle Scholar
  67. 67.
    Nakagawa S, Brennan C, Johnson KG et al. Ephrin-B regulates the Ipsilateral routing of retinal axons at the optic chiasm. Neuron 2000; 25:599–610.PubMedGoogle Scholar
  68. 68.
    Williams SE, Mann F, Erskine L et al. Ephrin-B2 and EphB1 mediate retinal axon divergence at the optic chiasm. Neuron 2003; 39:919–935.PubMedGoogle Scholar
  69. 69.
    Pak W, Hindges R, Lim YS et al. Magnitude of binocular vision controlled by islet-2 repression of a genetic program that specifies laterality of retinal axon pathfinding. Cell 2004; 119:567–578.PubMedGoogle Scholar
  70. 70.
    Williams SE, Mason CA, Herrera E. The optic chiasm as a midline choice point. Curr Opin Neurobiol 2004; 14:51–60.PubMedGoogle Scholar
  71. 71.
    Henkemeyer M, Orioli D, Henderson JT et al. Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell 1996; 86:35–46.PubMedGoogle Scholar
  72. 72.
    Orioli D, Henkemeyer M, Lemke G et al. Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation. EMBO J 1996; 15:6035–6049.PubMedGoogle Scholar
  73. 73.
    Hu Z, Yue X, Shi G et al. Corpus callosum deficiency in transgenic mice expressing a truncated ephrin-A receptor. J Neurosci 2003; 23:10963–10970.PubMedGoogle Scholar
  74. 74.
    Mendes SW, Henkemeyer M, Liebl DJ. Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing mouse forebrain. J Neurosci 2006; 26:882–892.PubMedGoogle Scholar
  75. 75.
    Sperry RW. Chemoaffinity in the orderly growth of nerve fiber patterns and connections. Proc Natl Acad Sci USA 1963; 50:703–710.PubMedGoogle Scholar
  76. 76.
    Cheng HJ, Nakamoto M, Bergemann AD et al. Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 1995; 82:371–381.PubMedGoogle Scholar
  77. 77.
    Drescher U, Kremoser C, Handwerker C et al. In vitro guidance of retinal ganglion cell axons by GAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell 1995; 82:359–370.PubMedGoogle Scholar
  78. 78.
    Feldheim DA, Kim YI, Bergemann AD et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 2000; 25:563–574.PubMedGoogle Scholar
  79. 79.
    Brown A, Yates PA, Burrola P et al. Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 2000; 102:77–88.PubMedGoogle Scholar
  80. 80.
    Reber M, Burrola P, Lemke G. A relative signalling model for the formation of a topographic neural map. Nature 2004; 431:847–853.PubMedGoogle Scholar
  81. 81.
    Hansen MJ, Dallal GE, Flanagan JG. Retinal axon response to ephrin-as shows a graded, concentration-dependent transition from growth promotion to inhibition. Neuron 2004; 42:717–730.PubMedGoogle Scholar
  82. 82.
    Rashid T, Upton AL, Blentic A et al. Opposing gradients of ephrin-As and EphA7 in the superior colliculus are essential for topographic mapping in the mammalian visual system. Neuron 2005; 47:57–69.PubMedGoogle Scholar
  83. 83.
    Hindges R, McLaughlin T, Genoud N et al. EphB forward signaling controls directional branch extension and arborization required for dorsal-ventral retinotopic mapping. Neuron 2002; 35:475–487.PubMedGoogle Scholar
  84. 84.
    McLaughlin T, Hindges R, Yates PA et al. Bifunctional action of ephrin-B1 as a repellent and attractant to control bidirectional branch extension in dorsal-ventral retinotopic mapping. Development 2003; 130:2407–2418.PubMedGoogle Scholar
  85. 85.
    Mann F, Peuckert C, Dehner F et al. Ephrins regulate the formation of terminal axonal arbors during the development of thalamocortical projections. Development 2002; 129:3945–3955.PubMedGoogle Scholar
  86. 86.
    Brittis PA, Lu Q, Flanagan JG. Axonal protein synthesis provides a mechanism for localized regulation at an intermediate target. Cell 2002; 110:223–235.PubMedGoogle Scholar
  87. 87.
    Feldheim DA, Vanderhaeghen P, Hansen MJ et al. Topographic guidance labels in a sensory projection to the forebrain. Neuron 1998; 21:1303–1313.PubMedGoogle Scholar
  88. 88.
    Ellsworth CA, Lyckman AW, Feldheim DA et al. Ephrin-A2 and-A5 influence patterning of normal and novel retinal projections to the thalamus: Conserved mapping mechanisms in visual and auditory thalamic targets. J Comp Neurol 2005; 488:140–151.PubMedGoogle Scholar
  89. 89.
    Pfeiffenberger C, Cutforth T, Woods G et al. Ephrin-As and neural activity are required for eye-specific patterning during retinogeniculate mapping. Nat Neurosci 2005; 8:1022–1027.PubMedGoogle Scholar
  90. 90.
    Huberman AD, Murray KD, Warland DK et al. Ephrin-As mediate targeting of eye-specific projections to the lateral geniculate nucleus. Nat Neurosci 2005; 8:1013–1021.PubMedGoogle Scholar
  91. 91.
    Bianchi LM, Gale NW. Distribution of Eph-related molecules in the developing and mature cochlea. Hear Res 1998; 117:161–172.PubMedGoogle Scholar
  92. 92.
    Nishida K, Flanagan JG, Nakamoto M. Domain-specific olivocerebellar projection regulated by the EphA-ephrin-A interaction. Development 2002; 129:5647–5658.PubMedGoogle Scholar
  93. 93.
    Lyckman AW, Jhaveri S, Feldheim DA et al. Enhanced plasticity of retinothalamic projections in an ephrin-A2/A5 double mutant. J Neurosci 2001; 21:7684–7690.PubMedGoogle Scholar
  94. 94.
    Cramer KS. Eph proteins and the assembly of auditory circuits. Hear Res 2005; 206:42–51.PubMedGoogle Scholar
  95. 95.
    Bianchi LM, Gray NA. EphB receptors influence growth of ephrin-B1-positive statoacoustic nerve fibers. Eur J Neurosci 2002; 16:1499–1506.PubMedGoogle Scholar
  96. 96.
    Cowan CA, Yokoyama N, Bianchi LM et al. EphB2 guides axons at the midline and is necessary for normal vestibular function. Neuron 2000; 26:417–430.PubMedGoogle Scholar
  97. 97.
    Person AL, Cerretti DP, Pasquale EB et al. Tonotopic gradients of Eph family proteins in the chick nucleus laminaris during synaptogenesis. J Neurobiol 2004; 60:28–39.PubMedGoogle Scholar
  98. 98.
    Siddiqui SA, Cramer KS. Differential expression of Eph receptors and ephrins in the cochlear ganglion and eighth cranial nerve of the chick embryo. J Comp Neurol 2005; 482:309–319.PubMedGoogle Scholar
  99. 99.
    Brors D, Bodmer D, Pak K et al. EphA4 provides repulsive signals to developing cochlear ganglion neurites mediated through ephrin-B2 and-B3. J Comp Neurol 2003; 462:90–100.PubMedGoogle Scholar
  100. 100.
    St John JA, Pasquale EB, Key B. EphA receptors and ephrin-A ligands exhibit highly regulated spatial and temporal expression patterns in the developing olfactory system. Brain Res Dev Brain Res 2002; 138:1–14.Google Scholar
  101. 101.
    Cutforth T, Moring L, Mendelsohn M et al. Axonal ephrin-As and odorant receptors: Coordinate determination of the olfactory sensory map. Cell 2003; 114:311–322.PubMedGoogle Scholar
  102. 102.
    Knöll B, Zarbalis K, Wurst W et al. A role for the EphA family in the topographic targeting of vomeronasal axons. Development 2001; 128:895–906.PubMedGoogle Scholar
  103. 103.
    Vanderhaeghen P, Polleux F. Developmental mechanisms patterning thalamocortical projections: Intrinsic, extrinsic and in between. Trends Neurosci 2004; 27:384–391.PubMedGoogle Scholar
  104. 104.
    Dufour A, Seibt J, Passante L et al. Area specificity and topography of thalamocortical projections are controlled by ephrin/Eph genes. Neuron 2003; 39:453–465.PubMedGoogle Scholar
  105. 105.
    Torii M, Levitt P. Dissociation of corticothalamic and thalamocortical axon targeting by an EphA7-mediated mechanism. Neuron 2005; 48:563–575.PubMedGoogle Scholar
  106. 106.
    Cang J, Kaneko M, Yamada J et al. Ephrin-as guide the formation of functional maps in the visual cortex. Neuron 2005; 48:577–589.PubMedGoogle Scholar
  107. 107.
    Castellani V, Yue Y, Gao PP et al. Dual action of a ligand for Eph receptor tyrosine kinases on specific populations of axons during the development of cortical circuits. J Neurosci 1998; 18:4663–4672.PubMedGoogle Scholar
  108. 108.
    Bolz J, Uziel D, Mühlfriedel S et al. Multiple roles of ephrins during the formation of thalamocortical projections: Maps and more. J Neurobiol 2004; 59:82–94.PubMedGoogle Scholar
  109. 109.
    Takemoto M, Fukuda T, Sonoda R et al. Ephrin-B3-EphA4 interactions regulate the growth of specific thalamocortical axon populations in vitro. Eur J Neurosci 2002; 16:1168–1172.PubMedGoogle Scholar
  110. 110.
    Pfaff S, Kintner C. Neuronal diversification: Development of motor neuron subtypes. Curr Opin Neurobiol 1998; 8:27–36.PubMedGoogle Scholar
  111. 111.
    Helmbacher F, Schneider-Maunoury S, Topilko P et al. Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development 2000; 127:3313–3324.PubMedGoogle Scholar
  112. 112.
    Kania A, Jessell TM. Topographic motor projections in the limb imposed by LIM homeodomain protein regulation of ephrin-A:EphA interactions. Neuron 2003; 38:581–596.PubMedGoogle Scholar
  113. 113.
    Eberhart J, Barr J, O’Connell S et al. Ephrin-A5 exerts positive or inhibitory effects on distinct subsets of EphA4-positive motor neurons. J Neurosci 2004; 24:1070–1078.PubMedGoogle Scholar
  114. 114.
    Vaidya A, Pniak A, Lemke G et al. EphA3 null mutants do not demonstrate motor axon guidance defects. Mol Cell Biol 2003; 23:8092–8098.PubMedGoogle Scholar
  115. 115.
    Gerlai R, McNamara A. Anesthesia induced retrograde ammesia is ameliorated by ephrinA5-IgG in mice: EphA receptor tyrosine kinases are involved in mammalian memory. Behav Brain Res 2000; 108:133–143.PubMedGoogle Scholar
  116. 116.
    Murai KK, Pasquale EB. Can Eph receptors stimulate the mind? Neuron 2002; 33:159–162.PubMedGoogle Scholar
  117. 117.
    Murai KK, Nguyen LN, Irie F et al. Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci 2003; 6:153–160.PubMedGoogle Scholar
  118. 118.
    Dalva MB, Takasu MA, Lin MZ et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 2000; 103:945–956.PubMedGoogle Scholar
  119. 119.
    Takasu MA, Dalva MB, Zigmond RE et al. Modulation of NMDA receptor-dependent calcium influx and gene expression through EphB receptors. Science 2002; 295:491–495.PubMedGoogle Scholar
  120. 120.
    Henkemeyer M, Itkis OS, Ngo M et al. Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J Cell Biol 2003; 163:1313–1326.PubMedGoogle Scholar
  121. 121.
    Ethell IM, Irie F, Kalo MS et al. EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 2001; 31:1001–1013.PubMedGoogle Scholar
  122. 122.
    Holmberg J, Armulik A, Senti KA et al. Ephrin-A2 reverse signaling negatively regulates neural progenitor proliferation and neurogenesis. Genes Dev 2005; 19:462–471.PubMedGoogle Scholar
  123. 123.
    Depaepe V, Suarez-Gonzalez N, Dufour A et al. Ephrin signalling controls brain size by regulating apoptosis of neural progenitors. Nature 2005; 435:1244–1250.PubMedGoogle Scholar
  124. 124.
    Koeberle PD, Bähr M. Growth and guidance cues for regenerating axons: Where have they gone? J Neurobiol 2004; 59:162–180.PubMedGoogle Scholar
  125. 125.
    Rodger J, Bartlett CA, Beazley LD et al. Transient upregulation of the rostrocaudal gradient of ephrin A2 in the tectum coincides with reestablishment of orderly projections during optic nerve regeneration in goldfish. Exp Neurol 2000; 166:196–200.PubMedGoogle Scholar
  126. 126.
    Symonds AC, Rodger J, Tan MM et al. Reinnervation of the superior colliculus delays down-regulation of ephrin A2 in neonatal rat. Exp Neurol 2001; 170:364–370.PubMedGoogle Scholar
  127. 127.
    Rodger J, Lindsey KA, Leaver SG et al. Expression of ephrin-A2 in the superior colliculus and EphA5 in the retina following optic nerve section in adult rat. Eur J Neurosci 2001; 14:1929–1936.PubMedGoogle Scholar
  128. 128.
    Rodger J, Vitale PN, Tee LB et al. EphA/ephrin-A interactions during optic nerve regeneration: Restoration of topography and regulation of ephrin-A2 expression. Mol Cell Neurosci 2004; 25:56–68.PubMedGoogle Scholar
  129. 129.
    Goldshmit Y, Galea MP, Wise G et al. Axonal regeneration and lack of astrocytic gliosis in EphA4-deficient mice. J Neurosci 2004; 24:10064–10073.PubMedGoogle Scholar
  130. 130.
    Irizarry-Ramírez M, Willson CA, Cruz-Orengo L et al. Upregulation of EphA3 receptor after spinal cord injury. J Neurotrauma 2005; 22:929–935.PubMedGoogle Scholar
  131. 131.
    Klagsbrun M, Eichmann A. A role for axon guidance receptors and ligands in blood vessel development and tumor angiogenesis. Cytokine Growth Factor Rev 2005; 16:535–548.PubMedGoogle Scholar
  132. 132.
    Tammela T, Petrova TV, Alitalo K. Molecular lymphangiogenesis: New players. Trends Cell Biol 2005; 15:434–441.PubMedGoogle Scholar
  133. 133.
    Wu J, Luo H. Recent advances on T-cell regulation by receptor tyrosine kinases. Curr Opin Hematol 2005; 12:292–297.PubMedGoogle Scholar
  134. 134.
    Wimmer-Kleikamp SH, Lackmann M. Eph-modulated cell morphology, adhesion and motility in carcinogenesis. IUBMB Life 2005; 57:421–431.PubMedGoogle Scholar
  135. 135.
    Surawska H, Ma PC, Salgia R. The role of ephrins and Eph receptors in cancer. Cytokine Growth Factor Rev 2004; 15:419–433.PubMedGoogle Scholar
  136. 136.
    Negrete OA, Levroney EI, Aguilar HC et al. EphrinB2 is the entry receptor for Nipah virus, an emergent deadly paramyxovirus. Nature 2005; 436:401–405.PubMedGoogle Scholar
  137. 137.
    Negrete OA, Wolf MC, Aguilar HC et al. Two key residues in Ephrinb3 are critical for its use as an alternative receptor for Nipah virus. PLoS Pathog 2006; 2:e7.PubMedGoogle Scholar
  138. 138.
    Dravis C, Yokoyama N, Chumley MJ et al. Bidirectional signaling mediated by ephrin-B2 and EphB2 controls urorectal development. Dev Biol 2004; 271:272–290.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2007

Authors and Affiliations

  • Michael Reber
    • 1
  • Robert Hindges
    • 2
  • Greg Lemke
    • 3
  1. 1.INSERM U.575Centre de NeurochimieStrasbourgFrance
  2. 2.MRC Centre for Developmental NeurobiologyKing’s College LondonLondonUK
  3. 3.Molecular Neurobiology LaboratoryThe Salk InstituteLa JollaUSA

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