Ephrins and Eph Receptor Tyrosine Kinases in Synapse Formation

  • Catherine E. KrullEmail author
  • Daniel J. Liebl


Here, we discuss what is known about the function of ephrins and Eph receptors in synapse formation in the peripheral nervous system and central nervous system. Ephrins have been shown to be present and functional at synapses at the neuromuscular junction and in the brain; evidence at the neuromuscular junction implicates ephrins in the topographic mapping of synapses on certain muscles. Also, certain Eph receptors also function in synapse formation but less information is known about them including their distribution and function. In addition, future directions are defined. Together, these data implicate ephrins, as well as Ephs, strongly in synaptic development.


Synaptogenesis Eph family PNS CNS 


  1. Adams RH, Wilkinson GA, Weiss C et al. (1999) Roles of ephrinB ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev 13:295–306CrossRefPubMedGoogle Scholar
  2. Arvanitis D and Davy A (2008) Eph/ephrin signaling: networks. Genes Dev 22:416–429CrossRefPubMedGoogle Scholar
  3. Buchert M, Schneider S, Meskenaite V et al. (1999) The junction-associated protein AF-6 interacts and clusters with specific Eph receptor tyrosine kinases at specialized sites of cell-cell contact in the brain. J Cell Biol 144:361–371CrossRefPubMedGoogle Scholar
  4. Bourgin C, Murai KK, Richter M et al. (2007) The EphA4 receptor regulates dendritic spine remodeling by affecting beta1-integrin signaling pathways. J Cell Biol 178:1295–1307CrossRefPubMedGoogle Scholar
  5. Chadaram SR, Laskowski MB and Madison RD (2007) Topographic specificity within membranes of a single muscle detected in vitro. J Neurosci 27:13938–13948CrossRefPubMedGoogle Scholar
  6. Chauvet S, Cohen S, Yoshida Y et al. (2007) Gating of Sema3E/PlexinD1 signaling by neuropilin-1 switches axonal repulsion to attraction during brain development. Neuron 56:807–822CrossRefPubMedGoogle Scholar
  7. Cheng HJ, Nakamoto M, Bergemann AD et al. (1995) Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82:371–381CrossRefPubMedGoogle Scholar
  8. Cowan CA and Henkemeyer M (2001) The SH2/SH3 adaptor Grb4 transduces B-ephrin reverse signals. Nature 413:174–179CrossRefPubMedGoogle Scholar
  9. Dailey ME and Smith SJ (1996) The dynamics of dendritic structure in developing hippocampal slices. J Neurosci 16:2983–2994PubMedGoogle Scholar
  10. Dalva MB, Takasu MA, Lin MZ et al. (2000) EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103:945–956CrossRefPubMedGoogle Scholar
  11. Davis S, Gale NW, Aldrich TH et al. (1994) Ligands for the Eph-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science 266:816–819CrossRefPubMedGoogle Scholar
  12. Davy A, Gale NW, Murray EW et al. (1999) Compartmentalized signaling by GPI-anchored ephrin-A5 requires the Fyn tyrosine kinase to regulate cellular adhesion. Genes Dev 13:3125–3135CrossRefPubMedGoogle Scholar
  13. Donoghue MJ, Merlie J and Sanes JR (1996) The Eph kinase ligand AL-1 is expressed by rostral muscles and inhibits outgrowth from caudal neurons. Mol Cell Neurosci 8:185–198CrossRefGoogle Scholar
  14. Dottori M, Hartley L, Galea M et al. (1998) EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. PNAS 95:13248–13253CrossRefPubMedGoogle Scholar
  15. Eberhart J, Swartz M, Koblar SA et al. (2000) Expression of EphA4, ephrin-A2 and ephrin-A5 during axon outgrowth to the hindlimb indicates potential roles in pathfinding. Dev Neurosci 22:237–250CrossRefPubMedGoogle Scholar
  16. Eberhart J, Barr J, O’Connell S et al. (2004) Ephrin-A5 exerts positive or inhibitory effects on distinct subsets of EphA4-positive motor neurons. J Neurosci 24:1070–1078CrossRefPubMedGoogle Scholar
  17. Eberhart J, Swartz ME, Koblar SA et al. (2002) EphA4 constitutes a population-specific guidance cue for motor neurons. Dev Biol 247:89–101CrossRefPubMedGoogle Scholar
  18. Egea J, Nissen UV, Dufour A et al. (2005) Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function. Neuron 47:515–528CrossRefPubMedGoogle Scholar
  19. Ethell IM, Irie F, Kalo MS et al. (2001) EphB/syndecan-2 signaling in dendritic spine morphogenesis. Neuron 31:1001–1013CrossRefPubMedGoogle Scholar
  20. Fanning AS and Anderson JM (1999) PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J Clin Invest 103:767–772CrossRefPubMedGoogle Scholar
  21. Feng G, Laskowski MB, Feldheim DA et al. (2000) Roles for ephrins in positionally selective synaptogenesis between motor neurons and muscle fibers. Neuron 25:295–306CrossRefPubMedGoogle Scholar
  22. Freywald A, Sharfe N and Roifman CM (2002) The kinase-null EphB6 receptor undergoes transphorylation in a complex with EphB1. J Biol Chem 277:3823–3828CrossRefPubMedGoogle Scholar
  23. Fu W-Y, Chen Y, Sahin M et al. (2007) Cdk5 regulates EphA4-mediated dendritic spine retraction through an ephexin1-dependent mechanism. Nat Neurosci 10:67–76CrossRefPubMedGoogle Scholar
  24. Gale NW, Flenniken A, Compton DC et al. (1996) Elk-3, a novel transmembrane ligand for the Eph family of receptor tyrosine kinases, expressed in embryonic floor plate, roof plate, and hindbrain segments. Oncogene 13:1343–1352PubMedGoogle Scholar
  25. Garcia SM, Casanueva MO, Silva MC et al. (2007) Neuronal signaling modulates protein homeostasis in Caenorhabditis elegans post-synaptic muscle cells. Genes Dev 21:3006–3016CrossRefPubMedGoogle Scholar
  26. Giger RJ, Cloutier JF, Sahay A et al. (2000) Neuropilin-2 is required in vivo for selective axon guidance responses to secreted semaphorins. Neuron 25:29–41CrossRefPubMedGoogle Scholar
  27. Grunwald IC, Korte M, Wolfer D et al. (2001) Kinase-independent requirement of EphB2 receptors in hippocampal synaptic plasticity. Neuron 32:1027–1040CrossRefPubMedGoogle Scholar
  28. Grunwald IC, Korte M, Adelmann G et al. (2004) Hippocampal plasticity requires postsynaptic ephrin-Bs. Nat Neurosci 7:33–40CrossRefPubMedGoogle Scholar
  29. Hattori M, Osterfield M and Flanagan JG (2000) Regulated cleavage of a contact-mediated axon repellent. Science 289:1360–1365CrossRefPubMedGoogle Scholar
  30. Helmbacher F, Schneider-Maunoury S, Topilko P et al. (2000) Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development 127:3313–3324PubMedGoogle Scholar
  31. Henkemeyer M, Orioli D, Henderson JT et al. (1996) Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell 86:35–46CrossRefPubMedGoogle Scholar
  32. Henkemeyer M, Itkis OS, Ngo M et al. (2003) Multiple EphB receptor tyrosine kinases shape dendritic spines in the hippocampus. J Cell Biol 163:1313–1326CrossRefPubMedGoogle Scholar
  33. Himanen JP, Saha N and Nikolov DB (2007) Cell-cell signaling via Eph receptors and ephrins. Curr Opin Cell Biol 19:534–542CrossRefPubMedGoogle Scholar
  34. Himanen JP, Chumley MJ, Lackmann M et al. (2004) Repelling class discrimination: ephrin-A5 binds to and activates EphB2 receptor signaling. Nat Neurosci 7:501–509CrossRefPubMedGoogle Scholar
  35. Hoogenraad CC, Milstein AD, Ethell IM et al. (2005) GRIP1 controls dendrite morphogenesis by regulating EphB receptor trafficking. Nat Neurosci 8:906–915PubMedGoogle Scholar
  36. Hu JY, Chen Y and Schacher S (2007) Multifunctional role of protein kinase C in regulating the formation and maturation of specific synapses. J Neurosci 27:11712–11724CrossRefPubMedGoogle Scholar
  37. Huber AB, Kania A, Tran TS et al. (2005) Distinct roles for secreted semaphoring signaling in spinal motor axon guidance. Neuron 48:949–964CrossRefPubMedGoogle Scholar
  38. Irie F, Okuno M, Pasquale EB et al. (2005) EphrinB-EphB signaling regulates clathrin-mediated endocytosis through tyrosine phosphorylation of synaptojanin 1. Nat Cell Biol 7:454–456CrossRefGoogle Scholar
  39. Irie F, Okumo M, Matsumoto K et al. (2008) Heparan sulfate regulates ephrin-A3/EphA receptor signaling. PNAS 34:12307–12312CrossRefGoogle Scholar
  40. Kayser MS, McClelland AC, Hughes EG et al. (2006) Intracellular and trans-synaptic regulation of glutamatergic synaptogenesis by EphB receptors. J Neurosci 26:12152–12164.CrossRefPubMedGoogle Scholar
  41. Kayser MS, Nolt MJ and Dalva MB (2008) EphB receptors couple dendritic filopodia motility to synapse formation. Neuron 59:56–69CrossRefPubMedGoogle Scholar
  42. Kania A, Johnson RL and Jessell TM (2000) Coordinate roles for LIM homeobox genes in directing dorsoventral trajectory of motor axons in the vertebrate limb. Cell 102:161–173CrossRefPubMedGoogle Scholar
  43. Kramer ER, Knott L, Su F et al. (2006) Cooperation between GDNF/Ret and ephrinA/EphA4 signals for motor axon pathway selection in the limb. Neuron 50:35–47CrossRefPubMedGoogle Scholar
  44. Krull CE, Lansford R, Gale NW et al. (1997) Interaction of Eph-related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration. Curr Biol 7:571–580CrossRefPubMedGoogle Scholar
  45. Kullander K and Klein R (2002) Mechanisms and functions of Eph and ephrin signaling. Nat Rev Mol Cell Biol 3:475–486CrossRefPubMedGoogle Scholar
  46. Kullander K, Mather NK, Diella F et al. (2001) Kinase-dependent and kinase-independent functions of EphA4 receptors in major axon tract formation in vivo. Neuron 29:73–84CrossRefPubMedGoogle Scholar
  47. Lackmann M, Oates AC, Dottori M et al. (1998) Distinct subdomains of the EphA3 receptor mediate ligand binding and receptor dimerization. J Biol Chem 273:20228–20237CrossRefPubMedGoogle Scholar
  48. Lampa SJ, Potluri S, Norton AS et al. (2004) Ephrin-A5 overexpression degrades topographic specificity in the mouse gluteus maximus muscle. Dev Brain Res 153:271–274CrossRefGoogle Scholar
  49. Lauterbach J and Klein R (2006) Release of full-length EphB2 receptors from hippocampal neurons to cocultured glial cells. J Neurosci 26:11575–11581CrossRefPubMedGoogle Scholar
  50. Liebl DJ, Morris CJ, Henkemeyer M et al. (2003) mRNA expression of ephrins and Eph receptor tyrosine kinases in the neonatal and adult mouse central nervous system. J Neurosci Res 71:7–22CrossRefPubMedGoogle Scholar
  51. Lim BK, Matsuda N and Poo MM (2008) Ephrin-B reverse signaling promotes structural and functional synaptic maturation in vivo. Nat Neurosci 11:160–169CrossRefPubMedGoogle Scholar
  52. Lin KT, Sloniowski S, Ethell DW et al. (2008) Ephrin-B2 induced cleavage of EphB2 receptor is mediated by matrix metalloproteinases to trigger cell repulsion. J Biol Chem. (Available online)Google Scholar
  53. Liu Z, Conroy WG, Stawicki TM et al. (2008) EphB receptors co-distribute with a nicotinic receptor subtype and regulate nicotinic downstream signaling in neurons. Mol Cell Neurosci 38:236–244CrossRefPubMedGoogle Scholar
  54. Lu Q, Sun EE, Klein RS et al. (2001) Ephrin-B reverse signaling is mediated by a novel PDZ-RGS protein and selectively inhibits G protein-coupled chemoattraction. Cell 105:69–79CrossRefPubMedGoogle Scholar
  55. Marston DJ, Dickinson S and Nobes CD (2003) Rac-dependent trans-endocytosis of ephrinBs regulates Eph-ephrin contact repulsion. Nat Cell Biol 5:879–888CrossRefPubMedGoogle Scholar
  56. McLaughlin T, Hindges R, Yates PA et al. (2003) Bifunctional action of ephrin-B1 as a repellent and attractant to control bidirectional branch extension in dorsal-ventral retinotopic mapping. Development 130:2407–2418CrossRefPubMedGoogle Scholar
  57. Mendes SW, Henkemeyer M and Liebl DJ (2006) Multiple Eph receptors and B-class ephrins regulate midline crossing of corpus callosum fibers in the developing mouse forebrain. J Neurosci 26:882–892CrossRefPubMedGoogle Scholar
  58. Migani P, Bartlett C, Dunlop S et al. (2007) Ephrin-B2 immunoreactivity distribution in the adult mouse brain. Brain Res 1182:60–72CrossRefPubMedGoogle Scholar
  59. Murai KK, Nguyen LN, Irie F et al. (2003) Control of hippocampal dendritic spine morphology through ephrin-A3/EphA4 signaling. Nat Neurosci 6:153–160CrossRefPubMedGoogle Scholar
  60. Murai KK and Pasquale EB (2004) Eph receptors, ephrins and synaptic function. The Neuroscientist 10:304–314CrossRefPubMedGoogle Scholar
  61. Nishida H and Okabe S (2007) Direct astrocytic contacts regulate local maturation of dendritic spines. J Neurosci 27:331–340CrossRefPubMedGoogle Scholar
  62. Pasquale EB (2008) Eph-ephrin bidirectional signaling in physiology and disease. Cell 133:38–52CrossRefPubMedGoogle Scholar
  63. Penzes P, Beeser A, Chernoff J et al. (2003) Rapid induction of dendritic spine morphogenesis by trans-synaptic ephrinB-EphB receptor activation of the Rho-GEF kalirin. Neuron 37:263–274CrossRefPubMedGoogle Scholar
  64. Rodenas-Ruano A, Perez-Pinzon MA, Green EJ et al. (2006) Distinct roles for ephrin-B3 in the formation and function of hippocampal synapses. Dev Biol 292:34–45CrossRefPubMedGoogle Scholar
  65. Sahin M, Greer PL, Lin MZ et al. (2005) Eph-dependent tyrosine phosphorylation of ephexin1 modulates growth cone collapse. Neuron 46:191–204CrossRefPubMedGoogle Scholar
  66. Sargiacomo M, Sudol M, Tang Z et al. (1993) Signal transducing molecules and glycosyl-phosphatidylinositol-linked proteins form a caveolin-rich insoluble complex in MDCK cells. J Cell Biol 122:789–807CrossRefPubMedGoogle Scholar
  67. Shenoy-Scaria AM, Dietzen DJ, Kwong J et al. (1994) Cysteine3 of Src family protein tyrosine kinase determines palmitoylation and localization in caveolae. J Cell Biol 126:353–363CrossRefPubMedGoogle Scholar
  68. Shintani T, Ihara M, Sakuta H et al. (2006) Eph receptors are negatively controlled by protein tyrosine phosphatase receptor type O. Nat Neurosci 9:761–769CrossRefPubMedGoogle Scholar
  69. Smith A, Robinson V, Patel K et al. (1997) The EphA4 and EphB1 receptor tyrosine kinases and ephrin-B2 ligand regulate targeted migration of brachial neural crest cells. Curr Biol 7:561–570CrossRefPubMedGoogle Scholar
  70. Stapleton D, Balan I, Pawson T et al. (1999) The crystal structure of an Eph receptor SAM domain reveals a mechanism for modular dimerization. Nat Struct Biol 6:44–49CrossRefPubMedGoogle Scholar
  71. Tolias KF, Bikoff JB, Kane CG et al. (2007) The Rac1 guanine nucleotide exchange factor Tiam1 mediates EphB receptor-dependent dendritic spine development. PNAS 104:7265–7270CrossRefPubMedGoogle Scholar
  72. Torres R, Firestein BL, Dong H et al. (1998) PDZ proteins bind, cluster and synaptically co-localize with Ephs and their ephrin ligands. Neuron 21:1227–1229CrossRefGoogle Scholar
  73. Thanos CD, Faham S, Goodwill KE et al. (1999) Monomeric structure of the human EphB2 sterile alpha motif domain. J Biol Chem 274:37301–37306CrossRefPubMedGoogle Scholar
  74. Wang HU and Anderson DJ (1997) Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18:383–396CrossRefPubMedGoogle Scholar
  75. Wang H, Chadaram SR, Norton AS et al. (2001) Development of inhibition by ephrin-A5 on outgrowth of embryonic spinal motor neurites. J Neurobiol 47:233–243CrossRefPubMedGoogle Scholar
  76. Wilkinson DG (2001) Multiple roles of EPH receptors and ephrins in neural development. Nat Rev Neurosci 2:155–164CrossRefPubMedGoogle Scholar
  77. Yamaguchi Y and Pasquale EB (2004) Eph receptors in the adult brain. Curr Opin Neurobiol 14:288–296CrossRefPubMedGoogle Scholar
  78. Zimmer M, Palmer A, Kohler J et al. (2003) EphB-ephrinB bi-directional endocytosis terminates adhesion allowing contact mediated repulsion. Nat Cell Biol 5:869–878CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2009

Authors and Affiliations

  1. 1.Biologic and Materials SciencesUniversity of Michigan, 5211 DentalAnn ArborUSA

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