Multiple roles of eph receptors and ephrins in neural development

Nature Reviews Neuroscience

Volumn 2, Issue 3, 2001, Pages 155-164

  Wilkinson, David G ^a  

^a NATIONAL INSTITUTE FOR MEDICAL RESEARCH   (United Kingdom)

Author keywords

[No Author keywords available]

Indexed keywords

EPHRIN RECEPTOR A1; LIGAND; MEMBRANE PROTEIN; PROTEIN TYROSINE KINASE;

ANIMAL; CELL MOTION; CHEMISTRY; GROWTH CONE; GROWTH, DEVELOPMENT AND AGING; METABOLISM; MORPHOGENESIS; NERVE CELL; NERVE FIBER; NERVOUS SYSTEM; PHYSIOLOGY; PRENATAL DEVELOPMENT; REVIEW; SIGNAL TRANSDUCTION;

ANIMALS; AXONS; BODY PATTERNING; CELL MOVEMENT; GROWTH CONES; LIGANDS; MEMBRANE PROTEINS; NERVOUS SYSTEM; NEURONS; RECEPTOR PROTEIN-TYROSINE KINASES; RECEPTOR, EPHA1; SIGNAL TRANSDUCTION;

EID: 0035287473     PISSN: 1471003X     EISSN: 14710048     Source Type: Journal    
DOI: 10.1038/35058515     Document Type: Article

References (120)

1. van der Geer, P, Hunter, T. & Lindberg, R. A. Receptor protein tyrosine kinases and their signal transduction pathways. Annu. Rev. Cell Biol. 10, 251-337 (1994).
2. Schlessinger, J. Cell signalling by receptor tyrosine kinases. Cell 103, 211-225 (2000).
3. Davis, S. et al. Ligands for EPH-related receptors that require membrane attachment or clustering for activity. Science 266, 816-819 (1994).
4. Gale, N. W. et al. Eph receptors and ligands comprise two major specificity subclasses, and are reciprocally compartmentalised during embryogenesis. Neuron 17, 9-19 (1996).
5. Henkemeyer, M. et al. Immunolocalisation of the Nuk receptor tyrosine kinase suggests roles in segmental patterning of the brain and axonogenesis. Oncogene 9, 1001-1014 (1994).
6. Holland, S. J. et al. Bidirectional signalling through the Eph- family receptor Nuk and its transmembrane ligands. Nature 383, 722-725 (1996).
7. Bruckner, K., Pasquale, E. B. & Klein, R. Tyrosine phosphorylation of transmembrane ligands for Eph receptors. Science 275, 1640-1643 (1997).
8. Henkemeyer, M. et al. Nuk controls pathfinding of commisural axons in the mammalian central nervous system. Cell 86, 35-46 (1996).
9. Davy, A. et al. Compartmentalized signaling by GPI-anchored ephrin-A5 requires the fyn tyrosine kinase to regulate cellular adhesion. Genes Dev. 13, 3125-3135 (1999).
10. Davy, A. & Robbins, S. M. Ephrin-A5 modulates cell adhesion and morphology in an integrin-dependent manner. EMBO J. 19, 5396-5405 (2000).
11. Wang, X et al. Multiple ephrins control cell organization in C. elegans through kinase-dependent and kinase-independent functions of the VAB-1 Eph receptor. Mol. Cell 4, 903-913 (1999).
12. Chin-Sang, I. D. et al. The ephrin VAB-2/EFN-1 functions in neuronal signaling to regulate epidermal morphogenesis in C. elegans. Cell 99, 781-790 (1999).
13. George, S. E., Simokat, K., Hardin, J. & Chisholm, A. D. The VAB-1 Eph receptor tyrosine kinase functions in neural and epithelial morphogenesis in C. elegans. Cell 92, 633-643 (1998).
14. Scully, A. L., McKeown, M. & Thomas, J. B. Isolation and characterization of Dek, a Drosophila Eph receptor protein tyrosine kinase. Mol. Cell. Neurosci. 13, 337-347 (1999).
15. Flanagan, J. G. & Vanderhaeghen, P. The ephrins and Eph receptors in neural development. Annu. Rev. Neurobiol. 21, 309-345 (1998).
16. Wilkinson, D. G. Eph receptors and ephrins: regulators of guidance and assembly. Int. Rev. Cyol. 196, 177-244 (2000).
17. Flenniken, A. M., Gale, N. W., Yancopoulos, G. D. & Wilkinson, D. G. Distinct and overlapping expression of ligands for Eph-related receptor tyrosine kinases during mouse embryogenesis. Dev. Biol. 179, 382-401 (1996).
18. Connor, R. J., Menzel, P. & Pasquale, E. B. Expression and tyrosine phosphorylation of Eph receptors suggest multiple mechanisms in patterning of the visual system. Dev. Biol. 193, 21-35 (1998).
19. Adams, R. H. et al. Roles of ephrin-B ligands and EphB receptors in cardiovascular development: demarcation of arterial/venous domains, vascular morphogenesis, and sprouting angiogenesis. Genes Dev. 13, 295-306 (1999).
20. Sobieszczuk, D. & Wilkinson, D. G. Masking by Eph receptors and ephrins. Curr. Biol. 9, R469-R470 (1999).
21. Hornberger, M. R. et al. Modulation of EphA receptor function by co-expressed ephrin-A ligands on retinal ganglion cell axons. Neuron 22, 731-742 (1999).
22. Wang, H. U. & Anderson, D. J. Eph family transmembrane ligands can mediate repulsive guidance of trunk neural crest migration and motor axon outgrowth. Neuron 18, 383-396 (1993).
23. Feldheim, D. A. et al. Topographic guidance labels in a sensory projection to the forebrain. Neuron 21, 1303-1313 (1993).
24. Monschau, B. et al. Shared and distinct functions of RAGS and ELF-1 in guiding retinal axons. EMBO J. 16, 1258-1267 (1997).
25. Fraser, S., Keynes, R. & Lumsden, A. Segmentation in the chick embryo hindbrain is defined by cell lineage restrictions. Nature 344, 431-435 (1990).
26. Takeichi, M. Cadherin cell adhesion receptors as a morphogenetic regulator. Science 251, 1451-1455 (1991)
27. Xu, Q., Alldus, G., Holder, N. & Wilkinson, D. G. Expression of truncated Sek-1 receptor tyrosine kinase disrupts the segmental restriction of gene expression in the Xenopus and zebrafish hindbrain. Development 121, 4005-4016 (1995).
28. Xu, Q., Mellitzer, G., Robinson, V. & Wilkinson, D. G. In vivo cell sorting in complementary segmental domains mediated by Eph receptors and ephrins. Nature 399, 267-271 (1999).
29. Mellitzer, G., Xu, Q. & Wilkinson, D. G. Restriction of cell intermingling and communication by Eph receptors and ephrins. Nature 400, 77-81 (1999).
30. Durbin, L. et al. Eph signaling is required for segmentation and differentiation of the somites. Genes Dev. 12, 3096-3109 (1998).
31. Robinson, V., Smith, A., Flenniken, A. M. & Wilkinson, D. G. Roles of Eph receptors and ephrins in neural crest pathfinding. Cell Tissue Res. 290, 265-274 (1997).
32. Kalcheim, C. & Teillet, M.-A. Consequences of somite manipulation on the pattern of dorsal root ganglion development. Development 106, 85-93 (1989).
33. Goldstein, R. S. & Kalcheim, C. Normal segmentation and size of the primary sympathetic ganglia depend upon the alternation of rostrocaudal properties of the somites. Development 112, 327-334 (1991).
34. Bronner-Fraser, M. & Stern, C. Effect of mesodermal tissues on avian neural crest cell migration. Dev. Biol. 143, 213-217 (1991).
35. Krull, C. E. et al. Interactions of Eph-related receptors and ligands confer rostrocaudal pattern to trunk neural crest migration. Curr. Biol. 7, 571-580 (1997).
36. Wang, H. U., Chen, Z.-F. & Anderson, D. J. Molecular distinction and angiogenic interaction between embryonic arteries and veins revealed by ephrin-B2 and its receptor EphB4. Cell 93, 741-753 (1998).
37. Kontges, G. & Lumsden, A. Rhombencephalic neural crest segmentation is preserved throughout craniofacial ontogeny. Development 122, 3229-3242 (1996).
38. Sadaghiani, B. & Thiebaud, C. H. Neural crest development in the Xenopus laevis embryo, studied by interspecific transplantation and scanning electron microscopy. Dev. Biol. 124, 91-110 (1987).
39. Smith, A., Robinson, V, Patel, K. & Wilkinson, D. G. The EphA4 and EphB1 receptor tyrosine kinases and ephrin-B2 ligand regulate targeted migration of branchial neural crest cells. Curr. Biol. 7, 561-570 (1997).
40. Tessier-Lavigne, M. & Goodman, C. S. The molecular biology of axon guidance. Science 274, 1123-1133 (1996).
41. Drescher, U. 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. Cell 82, 359-370 (1995).
42. Nakamoto, M. et al. Topographically specific effects of Elf-1 on retinal axon guidance in vitro and retinal axon mapping in vivo. Cell 86, 755-766 (1996).
43. Orioli, D., Henkemeyer, M., Lemke, G., Klein, R. & Pawson, T. Sek4 and Nuk receptors cooperate in guidance of commissural axons and in palate formation. EMBO J. 15, 6035-6049 (1996).
44. Park, S., Frisen, J. & Barbacid, M. Aberrant axonal projections in mice lacking EphA8 (Eek) tyrosine protein kinase receptors. EMBO J. 16, 3106-3114 (1997).
45. Dottori, M. et al. EphA4 (Sek1) receptor tyrosine kinase is required for the development of the corticospinal tract. Proc. Natl Acad. Sci. USA 95, 13248-13253 (1998).
46. Imondi, R., Wideman, C. & Kaprielian, Z. Complementary expression of transmembrane ephrins and their receptors in the mouse spinal cord: a possible role in constraining the orientation of longitudinally projecting axons. Development 127, 1397-1410 (2000).
47. Helmbacher, F., Schneider-Maunoury, S., Topilko, P., Tiret, L. & Charnay, P. Targeting of the EphA4 tyrosine kinase receptor affects dorsal/ventral pathfinding of limb motor axons. Development 127, 3313-3324 (2000).
48. Nakagawa, S. et al. Ephrin-B regulates the ipsilateral routing of retinal axons at the optic chiasm. Neuron 25, 599-610 (2000).
49. Knoll, B., Zarbalis, K., Dulac, C., Wurst, W. & Drescher, U. A role for the EphA family in the topographic targeting of vomeronasal axons. Development (in the press).
50. Gao, P. P. et al. Regulation of topographic projection in the brain: Elf-1 in the hippocamposeptal system. Proc. Natl Acad. Sci. USA 93, 11161-11166 (1996).
51. Gao, P.-P et al. Regulation of thalamic neurite growth by the Eph ligand ephrin-A5: Implications in the development of thalamocortical projections. Proc. Natl Acad. Sci. USA 95, 5329-5334 (1998).
52. Vanderhaegen, P. et al. A mapping label required for normal scale of body representation in the cortex. Nature Neurosci. 3, 358-365 (2000).
53. Feng, G. et al. Roles for ephrins in positionally selective synaptogenesis between motor neurons and muscle fibers. Neuron 25, 295-306 (2000).
54. Cheng, H.-J., Nakamoto, M., Bergemann, A. D. & Flanagan, J. G. Complementary gradients in expression and binding of ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell 82, 371-381 (1995).
55. Walkenhorst, J. et al. The EphA4 receptor tyrosine kinase is necessary for the guidance of nasal retinal ganglion cell axons in vitro. Mol. Cell. Neurosci. 16, 365-375 (2000).
56. Rosentreter, S. M. et al. Response of retinal ganglion cell axons to striped linear gradients of repellent guidance molecules. J. Neurobiol. 37, 541-562 (1998).
57. Frisen, J. et al. Ephrin-A5 (AL-1/RAGS) is essential for proper retinal axon guidance and topographic mapping in the mammalian visual system. Neuron 20, 235-243 (1998).
58. Feldheim, D. A. et al. Genetic analysis of ephrin-A2 and ephrin-A5 shows their requirement in multiple aspects of retinocollicular mapping. Neuron 25, 563-574 (2000).
59. Brown, A. et al. Topographic mapping from the retina to the midbrain is controlled by relative but not absolute levels of EphA receptor signaling. Cell 102, 77-88 (2000).
60. Roskies, A. L. & O'Leary, D. D. M. Control of topographic retinal axon branching by inhibitory membrane-bound molecules. Science 265, 799-803 (1994).
61. Gao, P. P., Yue, Y., Cerretti, D. P, Dreyfus, C. & Zhou, R. Ephrin-dependent growth and pruning of hippocampal axons. Proc. Natl Acad. Sci. USA 96, 4073-4077 (1999).
62. Castellani, V, Yue, Y, Gao, R-P., Zhou, R. & Bolz, J. Dual action of a ligand for Eph receptor tyrosine kinases on specific populations of axons during the development of cortical circuits. J. Neurosci. 18, 4663-4672 (1998).
63. Daniel, T. O. et al. ELK and LERK-2 in developing kidney and microvascular endothelial assembly. Kidney int. 50, S73-S81 (1996).
64. Stein, E. et al. Eph receptors discriminate specific ligand oligomers to determine alternative signaling complexes, attachment, and assembly responses. Genes Dev. 12, 667-678 (1998).
65. 1 integrins. EMBO J. 18, 2165-2173 (1999).
66. Pandey, A., Shao, H., Marks, R. M., Polverini, P. J. & Dixit, V M. Role of B61, the ligand for the Eck receptor tyrosine kinase, in TNF-a-induced angiogenesis. Science 268, 567-569 (1995).
67. Gerety, S. S., Wang, H. U., Chen, Z.-F. & Anderson, D. J. Symmetrical mutant phenotypes of the receptor EphB4 and its specific transmembrane ligand ephrin-B2 in cardiovascular development. Mol. Cell 4, 403-414 (1999).
68. Helbling, P M., Saulnier, D. M. E. & Brandli, A. W. The receptor tyrosine kinase EphB4 and ephrin-B ligands restrict angiogenic growth of embryonic veins in Xenopus laevis. Development 127, 269-278 (2000).
69. Holmberg, J., Clarke, D. L. & Frisen, J. Regulation of repulsion versus adhesion by different splice forms of an Eph receptor. Nature 408, 203-206 (2000).
70. Holash, J. A. & Pasquale, E. B. Polarized expression of the receptor protein-tyrosine kinase Cek5 in the developing avian visual system. Dev. Biol. 172, 683-693 (1995).
71. Braisted, J. E. et al. Graded and lamina-specific distributions of ligands of EphB receptor tyrosine kinases in the developing retinotectal system. Dev. Biol. 191, 14-28 (1997).
72. Holash, J. A. et al. Reciprocal expression of the Eph receptor Cek5 and its ligand(s) in the early retina. Dev. Biol. 182, 256-269 (1997).
73. Huai, J. & Drescher, U. An ephrinA-dependent signaling pathway controls integrin function and is linked to the tyrosine phosphorylation of a 120 kDa protein. J. Biol. Chem. (in the press).
74. Kalo, M. S. & Pasquale, E. B. Multiple in vivo tyrosine phosphorylation sites in EphB receptors. Biochemistry 38, 14396-14408 (1999).
75. Choi, S. & Park, S. Phosphorylation at Tyr-838 in the kinase domain of EphA8 modulates Fyn binding to the Tyr-615 site by enhancing tyrosine kinase activity. Oncogene 18, 5413-5422 (1999).
76. Zisch, A. H. et al. Replacing two conserved tyrosine residues of the EphB2 receptor with glutamic acid prevents binding of SH2 domains without abrogating kinase activity and biological responses. Oncogene 19, 177-187 (2000).
77. Binns, K. L., Taylor, P P., Sicheri, F., Pawson, T. & Holland, S. J. Phosphorylation of tyrosine residues in the kinase domain and juxtamembrane region regulates the biological and catalytic activities of Eph receptors. Mol. Cell. Biol. 20, 4791-4805 (2000).
78. Bruckner, K. & Klein, R. Signaling by Eph receptors and their ephrin ligands. Curr. Opin. Neurobiol. 8, 375-382 (1998).
79. Holland, S. J., Peles, E., Pawson, T & Schlessinger, J. Cell- contact-dependent signalling in axon growth and guidance: Eph receptor tyrosine kinases and receptor protein tyrosine phosphatase b. Curr. Opin. Neurobiol. 8, 117-127 (1998).
80. Mellitzer, G., Xu, Q. & Wilkinson, D. G. Control of cell behaviour by signalling through Eph receptors and ephrins. Curr. Opin. Neurobiol. 10, 400-408 (2000).
81. Ellis, C. et al. A juxtamembrane autophosphorylation site in the Eph family receptor tyrosine kinase, Sek, mediates high affinity interaction with p59fyn. Oncogene 12, 1727-1736 (1996).
82. Holland, S. J. et al. Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. EMBO J. 16, 3877-3888 (1997).
83. Zisch, A. H., Kalo, M. S., Chong, L. D. & Pasquale, E. B. Complex formation between EphB2 and Src requires phosphorylation of tyrosine 611 in the EphB2 juxtamembrane region. Oncogene 16, 2657-2670 (1998).
84. Hock, B. et al. Tyrosine-614, the major autophosphorylation site of the receptor tyrosine kinase HEK2, functions as multi- docking site for SH2-domain mediated interactions. Oncogene 17, 255-260 (1998).
85. Zisch, A. H. et al. Tyrosine phosphorylation of L1 family adhesion molecules: implication of the Eph kinase Cek5. J. Neurosci. Res. 47, 655-665 (1997).
86. Hock, B. et al. PDZ-domain-mediated interaction of the Eph-related receptor tyrosine kinase EphB3 and the ras- binding protein AF6 depends on the kinase activity of the receptor. Proc. Natl Acad. Sci. USA 95, 9779-9784 (1998).
87. Bruckner, K. et al. EphrinB ligands recruit GRIP family PDZ adaptor proteins into raft membrane microdomains. Neuron 22, 511-524 (1999).
88. Torres, R. et al. PDZ domains bind, cluster, and synaptically co-localize with Eph receptors and their ephrin ligands. Neuron 21, 1453-1463 (1998).
89. Buchert, M. et al. The junction-associated protein AF-6 interacts and clusters with specific Eph receptor tyrosine kinases at specialised sites of cell-cell contact in the brain. J. Cell Biol. 144, 361-371 (1999).
90. Lin, D., Gish, G. D., Songyang, Z. & Pawson, T. The carboxyl terminus of B class ephrins constitutes a PDZ domain binding motif. J. Biol. Chem. 274, 3726-3733 (1999).
91. Meima, L. et al. AL-1-induced growth cone collapse of rat cortical neurons is correlated with REK7 expression and rearrangement of the actin cytoskeleton. Eur. J. Neurosci. 9, 177-188 (1997).
92. Wahl, S., Barth, H., Ciossek, T., Aktories, K. & Mueller, B. K. Ephrin-A5 induces collapse of growth cones by activating rho and rtio kinase. J. Cell Biol. 149, 263-270 (2000).
93. Winning, R. S., Scales, J. B. & Sargent, T D. Disruption of cell adhesion in Xenopus embryos by Pagliaccio, an Eph-class receptor tyrosine kinase. Dev. Biol. 179, 309-319 (1996).
94. Jones, T. L. et al. Loss of cell adhesion in Xenopus laevis embryos mediated by the cytoplasmic domain of XLerk, an erythropoietin-producing hepatocellular ligand. Proc. Natl Acad. Sci. USA 95, 576-581 (1998).
95. Miao, H., Burnett, E., Kinch, M., Simon, E. & Wang, B. Activation of EphA2 kinase suppresses integrin function and causes focal adhesion kinase dephosphorylation. Nature Cell Biol. 2, 62-69 (2000).
96. Dodelet, V C., Pazzagli, C., Zisch, A. H., Hauser, C. A. & Pasquale, E. B. A novel signaling intermediate, SHEP1, directly couples Eph receptors to R-Ras and Rap1A. J. Biol. Chem. 274, 31941-31946 (1999).
97. Hattori, M., Osterfield, M. & Flanagan, J. G. Regulated cleavage of a contact-mediated axon repellent. Science 289, 1360-1365 (2000).
98. Stein, E., Huynh-Do, U., Lane, A. A., Ceretti, D. P. & Daniel, T. D. Nck recruitment to Eph receptor, EphB1/Elk, couples ligand activation to c-Jun kinase. J. Biol. Chem. 273, 1303-1308 (1998).
99. Becker, E. et al. Nck-interacting Ste20 kinase couples Eph receptors to c-Jun N-terminal kinase and integrin activation. Mol. Cell. Biol. 20, 1537-1545 (2000).
100. Gao, P P, Sun, C. H., Zhou, X. F., DiCicco-Bloom, E. & Zhou, R. P. Ephrins stimulate or inhibit neurite outgrowth and survival as a function of neuronal cell type. J. Neurosci. Res. 60, 427-436 (2000).
101. Gale, N. W. & Yancopoulos, G. D. Ephrins and their receptors: a repulsive topic? Cell Tissue Res. 290, 227-241 (1993).
102. Ciossek, T., Ullrich, A., West, E. & Rogers, J. H. Segregation of the receptor EphA7 from its tyrosine kinase-negative isoform on neurons in adult mouse brain. Mol. Brain Res. 74, 231-236 (1999).
103. Chong, L. D., Park, E. K., Latimer, E., Friesel, R. & Daar, I. O. Fibroblast growth factor receptor-mediated rescue of x- ephrin B1-induced cell dissociation in Xenopus embryos. Mol. Cell. Biol. 20, 724-734 (2000).
104. Oates, A. C. et al. An early developmental role for Eph-ephrin interaction during vertebrate gastrulation. Mech. Dev. 83, 77-94 (1999).
105. Gao, W. Q. et al. Regulation of hippocampal synaptic plasticity by the tyrosine kinase receptor, REK7/EphA5, and its ligand, AL-1/ephrin-A5. Mol. Cell. Neurosci. 11, 247-259 (1998).
106. Gerlai, R. et al. Regulation of learning by EphA receptors: a protein targeting study. J. Neurosci. 19, 9538-9549 (1999).
107. Dalva, M. B. et al. EphB receptors interact with NMDA receptors and regulate excitatory synapse formation. Cell 103, 945-956 (2000).
108. Zantek, N. D. et al. E-cadherin regulates the function of the EphA2 receptor tyrosine kinase. Cell Growth Diff. 10, 629-638 (1999).
109. Orsulic, S. & Kemler, R. Expression of Eph receptors and ephrins is differentially regulated by E-cadherin. J. Cell Science 113, 1793-1802 (2000).
110. Halford, M. H. et al. Ryk-deficient mice exhibit craniofacial defects associated with perturbed Eph receptor crosstalk. Nature Genet. 25, 414-418 (2000).
111. Zallen, J. A., Kirch, S. A. & Bargmann, C. I. Genes required for axon pathfinding and extension in C. elegans nerve ring. Development 126, 3679-3692 (1999).
112. Cowan, C. A., Yokoyama, N., Bianchi, L. M., Henkemeyer M. & Fritzch, B. EphB2 guides axons at the midline and is necessary for normal vestibular function. Neuron 26, 417-430 (2000).
113. Brambilla, R. et al. Membrane-bound LERK2 ligand can signal through three different Eph-related receptor tyrosine kinases. EMBO J. 14, 3116-3126 (1995).
114. Yue, Y. et al. Selective inhibition of spinal cord neurite outgrowth and cell survival by the Eph family ligand ephrin- A5. J. Neurosci. 19, 10026-10035 (1999).
115. Fulton, B. P Gap junctions in the developing nervous system. Perspect. Dev. Neurobiol. 2, 327-334 (1995).
116. Martinez, S., Geijo, E., Sanchez-Vives, M. V., Puelles, L. & Gallego, R. Reduced junctional permeability at interrhombomeric boundaries. Development 116, 1069-1076 (1992).
117. Lhotak, V & Pawson, T. Biological and biochemical activities of a chimeric epidermal growth factor-Elk receptor tyrosine kinase. Mol. Cell. Biol. 13, 7071-7079 (1993).
118. Andres, A.-C. et al. Expression of two novel eph-related receptor protein tyrosine kinases in mammary gland development and carcinogenesis. Oncogene 9, 1461-1467 (1994).
119. Vogt, T et al. Overexpression of Lerk-5/Eplg5 messenger RNA: a novel marker for increased tumorigenicity and metastatic potential in human malignant melanomas. Clin. Cancer Res. 4, 791-797 (1998).
120. Tang, X. X. et al. Implications of EPHB6, EFNB2, and EFNB3 expressions in human neuroblastoma. Proc. Natl Acad. Sci. USA 97, 10936-10941 (2000).