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. 1997 Jun 2;16(11):3106–3114. doi: 10.1093/emboj/16.11.3106

Aberrant axonal projections in mice lacking EphA8 (Eek) tyrosine protein kinase receptors.

S Park 1, J Frisén 1, M Barbacid 1
PMCID: PMC1169929  PMID: 9214628

Abstract

We have generated mice homozygous for a mutation that disrupts the gene encoding EphA8, a member of the Eph family of tyrosine protein kinase receptors, previously known as Eek. These mice develop to term, are fertile and do not display obvious anatomical or physiological defects. The mouse ephA8/eek gene is expressed primarily in a rostral to caudal gradient in the developing tectum. Axonal tracing experiments have revealed that in these mutant mice, axons from a subpopulation of tectal neurons located in the superficial layers of the superior colliculus do not reach targets located in the contralateral inferior colliculus. Moreover, ephA8/eek null animals display an aberrant ipsilateral axonal tract that projects to the ventral region of the cervical spinal cord. Retrograde labeling revealed that these abnormal projections originate from a small subpopulation of superior colliculus neurons that normally express the ephA8/eek gene. These results suggest that EphA8/Eek receptors play a role in axonal pathfinding during development of the mammalian nervous system.

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Selected References

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  1. Becker N., Seitanidou T., Murphy P., Mattéi M. G., Topilko P., Nieto M. A., Wilkinson D. G., Charnay P., Gilardi-Hebenstreit P. Several receptor tyrosine kinase genes of the Eph family are segmentally expressed in the developing hindbrain. Mech Dev. 1994 Jul;47(1):3–17. doi: 10.1016/0925-4773(94)90091-4. [DOI] [PubMed] [Google Scholar]
  2. Bergemann A. D., Cheng H. J., Brambilla R., Klein R., Flanagan J. G. ELF-2, a new member of the Eph ligand family, is segmentally expressed in mouse embryos in the region of the hindbrain and newly forming somites. Mol Cell Biol. 1995 Sep;15(9):4921–4929. doi: 10.1128/mcb.15.9.4921. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Bouillet P., Oulad-Abdelghani M., Vicaire S., Garnier J. M., Schuhbaur B., Dollé P., Chambon P. Efficient cloning of cDNAs of retinoic acid-responsive genes in P19 embryonal carcinoma cells and characterization of a novel mouse gene, Stra1 (mouse LERK-2/Eplg2). Dev Biol. 1995 Aug;170(2):420–433. doi: 10.1006/dbio.1995.1226. [DOI] [PubMed] [Google Scholar]
  4. Chan J., Watt V. M. eek and erk, new members of the eph subclass of receptor protein-tyrosine kinases. Oncogene. 1991 Jun;6(6):1057–1061. [PubMed] [Google Scholar]
  5. 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. 1995 Aug 11;82(3):371–381. doi: 10.1016/0092-8674(95)90426-3. [DOI] [PubMed] [Google Scholar]
  6. Ciossek T., Lerch M. M., Ullrich A. Cloning, characterization, and differential expression of MDK2 and MDK5, two novel receptor tyrosine kinases of the eck/eph family. Oncogene. 1995 Nov 16;11(10):2085–2095. [PubMed] [Google Scholar]
  7. Drescher U., Kremoser C., Handwerker C., Löschinger J., Noda M., Bonhoeffer F. In vitro guidance of retinal ganglion cell axons by RAGS, a 25 kDa tectal protein related to ligands for Eph receptor tyrosine kinases. Cell. 1995 Aug 11;82(3):359–370. doi: 10.1016/0092-8674(95)90425-5. [DOI] [PubMed] [Google Scholar]
  8. Gale N. W., Holland S. J., Valenzuela D. M., Flenniken A., Pan L., Ryan T. E., Henkemeyer M., Strebhardt K., Hirai H., Wilkinson D. G. Eph receptors and ligands comprise two major specificity subclasses and are reciprocally compartmentalized during embryogenesis. Neuron. 1996 Jul;17(1):9–19. doi: 10.1016/s0896-6273(00)80276-7. [DOI] [PubMed] [Google Scholar]
  9. Gao P. P., Zhang J. H., Yokoyama M., Racey B., Dreyfus C. F., Black I. B., Zhou R. Regulation of topographic projection in the brain: Elf-1 in the hippocamposeptal system. Proc Natl Acad Sci U S A. 1996 Oct 1;93(20):11161–11166. doi: 10.1073/pnas.93.20.11161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Gonzalez-Hernandez T. H., Meyer G., Ferres-Torres R., Castañeyra-Perdomo A., del Mar Perez Delgado M. Afferent connections of the inferior colliculus in the albino mouse. J Hirnforsch. 1987;28(3):315–323. [PubMed] [Google Scholar]
  11. Gurniak C. B., Berg L. J. A new member of the Eph family of receptors that lacks protein tyrosine kinase activity. Oncogene. 1996 Aug 15;13(4):777–786. [PubMed] [Google Scholar]
  12. Henkemeyer M., Marengere L. E., McGlade J., Olivier J. P., Conlon R. A., Holmyard D. P., Letwin K., Pawson T. Immunolocalization of the Nuk receptor tyrosine kinase suggests roles in segmental patterning of the brain and axonogenesis. Oncogene. 1994 Apr;9(4):1001–1014. [PubMed] [Google Scholar]
  13. Henkemeyer M., Orioli D., Henderson J. T., Saxton T. M., Roder J., Pawson T., Klein R. Nuk controls pathfinding of commissural axons in the mammalian central nervous system. Cell. 1996 Jul 12;86(1):35–46. doi: 10.1016/s0092-8674(00)80075-6. [DOI] [PubMed] [Google Scholar]
  14. Holland S. J., Gale N. W., Mbamalu G., Yancopoulos G. D., Henkemeyer M., Pawson T. Bidirectional signalling through the EPH-family receptor Nuk and its transmembrane ligands. Nature. 1996 Oct 24;383(6602):722–725. doi: 10.1038/383722a0. [DOI] [PubMed] [Google Scholar]
  15. Martin-Zanca D., Oskam R., Mitra G., Copeland T., Barbacid M. Molecular and biochemical characterization of the human trk proto-oncogene. Mol Cell Biol. 1989 Jan;9(1):24–33. doi: 10.1128/mcb.9.1.24. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Mullen R. J., Buck C. R., Smith A. M. NeuN, a neuronal specific nuclear protein in vertebrates. Development. 1992 Sep;116(1):201–211. doi: 10.1242/dev.116.1.201. [DOI] [PubMed] [Google Scholar]
  17. Nakamoto M., Cheng H. J., Friedman G. C., McLaughlin T., Hansen M. J., Yoon C. H., O'Leary D. D., Flanagan J. G. Topographically specific effects of ELF-1 on retinal axon guidance in vitro and retinal axon mapping in vivo. Cell. 1996 Sep 6;86(5):755–766. doi: 10.1016/s0092-8674(00)80150-6. [DOI] [PubMed] [Google Scholar]
  18. O'Leary D. D., Koester S. E. Development of projection neuron types, axon pathways, and patterned connections of the mammalian cortex. Neuron. 1993 Jun;10(6):991–1006. doi: 10.1016/0896-6273(93)90049-w. [DOI] [PubMed] [Google Scholar]
  19. Pandey A., Lindberg R. A., Dixit V. M. Cell signalling. Receptor orphans find a family. Curr Biol. 1995 Sep 1;5(9):986–989. doi: 10.1016/s0960-9822(95)00195-3. [DOI] [PubMed] [Google Scholar]
  20. SPERRY R. W. CHEMOAFFINITY IN THE ORDERLY GROWTH OF NERVE FIBER PATTERNS AND CONNECTIONS. Proc Natl Acad Sci U S A. 1963 Oct;50:703–710. doi: 10.1073/pnas.50.4.703. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Sajjadi F. G., Pasquale E. B. Five novel avian Eph-related tyrosine kinases are differentially expressed. Oncogene. 1993 Jul;8(7):1807–1813. [PubMed] [Google Scholar]
  22. Tessier-Lavigne M. Eph receptor tyrosine kinases, axon repulsion, and the development of topographic maps. Cell. 1995 Aug 11;82(3):345–348. doi: 10.1016/0092-8674(95)90421-2. [DOI] [PubMed] [Google Scholar]
  23. Tuzi N. L., Gullick W. J. eph, the largest known family of putative growth factor receptors. Br J Cancer. 1994 Mar;69(3):417–421. doi: 10.1038/bjc.1994.77. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Tybulewicz V. L., Crawford C. E., Jackson P. K., Bronson R. T., Mulligan R. C. Neonatal lethality and lymphopenia in mice with a homozygous disruption of the c-abl proto-oncogene. Cell. 1991 Jun 28;65(7):1153–1163. doi: 10.1016/0092-8674(91)90011-m. [DOI] [PubMed] [Google Scholar]

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