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. 1997 Mar 17;16(6):1258–1267. doi: 10.1093/emboj/16.6.1258

Shared and distinct functions of RAGS and ELF-1 in guiding retinal axons.

B Monschau 1, C Kremoser 1, K Ohta 1, H Tanaka 1, T Kaneko 1, T Yamada 1, C Handwerker 1, M R Hornberger 1, J Löschinger 1, E B Pasquale 1, D A Siever 1, M F Verderame 1, B K Müller 1, F Bonhoeffer 1, U Drescher 1
PMCID: PMC1169724  PMID: 9135142

Abstract

Two ligands for Eph-related receptor tyrosine kinases, RAGS and ELF-1, have been implicated in the control of development of the retinotectal projection. Both molecules are expressed in overlapping gradients in the tectum, the target area of retinal ganglion cell axons. In two in vitro assays ELF-1 is shown to have a repellent axon guidance function for temporal, but apparently not for nasal axons. RAGS on the other hand is repellent for both types of axons, though to different degrees. Thus, RAGS and ELF-1 share some and differ in other properties. The biological activities of these molecules correlate with the strength of interaction with their receptors expressed on RGC axons. The meaning of these findings for guidance of retinal axons in the tectum is discussed.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Beckmann M. P., Cerretti D. P., Baum P., Vanden Bos T., James L., Farrah T., Kozlosky C., Hollingsworth T., Shilling H., Maraskovsky E. Molecular characterization of a family of ligands for eph-related tyrosine kinase receptors. EMBO J. 1994 Aug 15;13(16):3757–3762. doi: 10.1002/j.1460-2075.1994.tb06685.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Bennett B. D., Zeigler F. C., Gu Q., Fendly B., Goddard A. D., Gillett N., Matthews W. Molecular cloning of a ligand for the EPH-related receptor protein-tyrosine kinase Htk. Proc Natl Acad Sci U S A. 1995 Mar 14;92(6):1866–1870. doi: 10.1073/pnas.92.6.1866. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. 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]
  4. Brambilla R., Klein R. Telling axons where to grow: a role for Eph receptor tyrosine kinases in guidance. Mol Cell Neurosci. 1995 Dec;6(6):487–495. doi: 10.1006/mcne.1995.0001. [DOI] [PubMed] [Google Scholar]
  5. Brambilla R., Schnapp A., Casagranda F., Labrador J. P., Bergemann A. D., Flanagan J. G., Pasquale E. B., Klein R. Membrane-bound LERK2 ligand can signal through three different Eph-related receptor tyrosine kinases. EMBO J. 1995 Jul 3;14(13):3116–3126. doi: 10.1002/j.1460-2075.1995.tb07314.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  6. 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]
  7. Cox E. C., Müller B., Bonhoeffer F. Axonal guidance in the chick visual system: posterior tectal membranes induce collapse of growth cones from the temporal retina. Neuron. 1990 Jan;4(1):31–37. doi: 10.1016/0896-6273(90)90441-h. [DOI] [PubMed] [Google Scholar]
  8. Davis S., Gale N. W., Aldrich T. H., Maisonpierre P. C., Lhotak V., Pawson T., Goldfarb M., Yancopoulos G. D. Ligands for EPH-related receptor tyrosine kinases that require membrane attachment or clustering for activity. Science. 1994 Nov 4;266(5186):816–819. doi: 10.1126/science.7973638. [DOI] [PubMed] [Google Scholar]
  9. 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]
  10. Flanagan J. G., Leder P. The kit ligand: a cell surface molecule altered in steel mutant fibroblasts. Cell. 1990 Oct 5;63(1):185–194. doi: 10.1016/0092-8674(90)90299-t. [DOI] [PubMed] [Google Scholar]
  11. Ganju P., Shigemoto K., Brennan J., Entwistle A., Reith A. D. The Eck receptor tyrosine kinase is implicated in pattern formation during gastrulation, hindbrain segmentation and limb development. Oncogene. 1994 Jun;9(6):1613–1624. [PubMed] [Google Scholar]
  12. Goodman C. S. Mechanisms and molecules that control growth cone guidance. Annu Rev Neurosci. 1996;19:341–377. doi: 10.1146/annurev.ne.19.030196.002013. [DOI] [PubMed] [Google Scholar]
  13. Holash J. A., Pasquale E. B. Polarized expression of the receptor protein tyrosine kinase Cek5 in the developing avian visual system. Dev Biol. 1995 Dec;172(2):683–693. doi: 10.1006/dbio.1995.8039. [DOI] [PubMed] [Google Scholar]
  14. Holt C. E., Harris W. A. Position, guidance, and mapping in the developing visual system. J Neurobiol. 1993 Oct;24(10):1400–1422. doi: 10.1002/neu.480241011. [DOI] [PubMed] [Google Scholar]
  15. Kozlosky C. J., Maraskovsky E., McGrew J. T., VandenBos T., Teepe M., Lyman S. D., Srinivasan S., Fletcher F. A., Gayle R. B., 3rd, Cerretti D. P. Ligands for the receptor tyrosine kinases hek and elk: isolation of cDNAs encoding a family of proteins. Oncogene. 1995 Jan 19;10(2):299–306. [PubMed] [Google Scholar]
  16. Lindberg R. A., Hunter T. cDNA cloning and characterization of eck, an epithelial cell receptor protein-tyrosine kinase in the eph/elk family of protein kinases. Mol Cell Biol. 1990 Dec;10(12):6316–6324. doi: 10.1128/mcb.10.12.6316. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Lumsden A. The cellular basis of segmentation in the developing hindbrain. Trends Neurosci. 1990 Aug;13(8):329–335. doi: 10.1016/0166-2236(90)90144-y. [DOI] [PubMed] [Google Scholar]
  18. Maisonpierre P. C., Barrezueta N. X., Yancopoulos G. D. Ehk-1 and Ehk-2: two novel members of the Eph receptor-like tyrosine kinase family with distinctive structures and neuronal expression. Oncogene. 1993 Dec;8(12):3277–3288. [PubMed] [Google Scholar]
  19. McLoon S. C. A monoclonal antibody that distinguishes between temporal and nasal retinal axons. J Neurosci. 1991 May;11(5):1470–1477. doi: 10.1523/JNEUROSCI.11-05-01470.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Mey J., Thanos S. Development of the visual system of the chick--a review. J Hirnforsch. 1992;33(6):673–702. [PubMed] [Google Scholar]
  21. 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]
  22. 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-alpha-induced angiogenesis. Science. 1995 Apr 28;268(5210):567–569. doi: 10.1126/science.7536959. [DOI] [PubMed] [Google Scholar]
  23. Rager G. Morphogenesis and physiogenesis of the retino-tectal connection in the chicken. II. The retino-tectal synapses. Proc R Soc Lond B Biol Sci. 1976 Feb 17;192(1108):353–370. doi: 10.1098/rspb.1976.0018. [DOI] [PubMed] [Google Scholar]
  24. Raper J. A., Kapfhammer J. P. The enrichment of a neuronal growth cone collapsing activity from embryonic chick brain. Neuron. 1990 Jan;4(1):21–29. doi: 10.1016/0896-6273(90)90440-q. [DOI] [PubMed] [Google Scholar]
  25. Roskies A., Friedman G. C., O'Leary D. D. Mechanisms and molecules controlling the development of retinal maps. Perspect Dev Neurobiol. 1995;3(1):63–75. [PubMed] [Google Scholar]
  26. 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]
  27. Savitt J. M., Trisler D., Hilt D. C. Molecular cloning of TOPAP: a topographically graded protein in the developing chick visual system. Neuron. 1995 Feb;14(2):253–261. doi: 10.1016/0896-6273(95)90283-x. [DOI] [PubMed] [Google Scholar]
  28. Shao H., Lou L., Pandey A., Verderame M. F., Siever D. A., Dixit V. M. cDNA cloning and characterization of a Cek7 receptor protein-tyrosine kinase ligand that is identical to the ligand (ELF-1) for the Mek-4 and Sek receptor protein-tyrosine kinases. J Biol Chem. 1995 Feb 24;270(8):3467–3470. doi: 10.1074/jbc.270.8.3467. [DOI] [PubMed] [Google Scholar]
  29. Siever D. A., Verderame M. F. Identification of a complete Cek7 receptor protein tyrosine kinase coding sequence and cDNAs of alternatively spliced transcripts. Gene. 1994 Oct 21;148(2):219–226. doi: 10.1016/0378-1119(94)90692-0. [DOI] [PubMed] [Google Scholar]
  30. 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]
  31. Walter J., Kern-Veits B., Huf J., Stolze B., Bonhoeffer F. Recognition of position-specific properties of tectal cell membranes by retinal axons in vitro. Development. 1987 Dec;101(4):685–696. doi: 10.1242/dev.101.4.685. [DOI] [PubMed] [Google Scholar]
  32. Whitelaw V. A., Cowan J. D. Specificity and plasticity of retinotectal connections: a computational model. J Neurosci. 1981 Dec;1(12):1369–1387. doi: 10.1523/JNEUROSCI.01-12-01369.1981. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Wilkinson D. G. RNA detection using non-radioactive in situ hybridization. Curr Opin Biotechnol. 1995 Feb;6(1):20–23. doi: 10.1016/0958-1669(95)80004-2. [DOI] [PubMed] [Google Scholar]
  34. Willshaw D. J., von der Malsburg C. How patterned neural connections can be set up by self-organization. Proc R Soc Lond B Biol Sci. 1976 Nov 12;194(1117):431–445. doi: 10.1098/rspb.1976.0087. [DOI] [PubMed] [Google Scholar]
  35. 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. 1995 Dec;121(12):4005–4016. doi: 10.1242/dev.121.12.4005. [DOI] [PubMed] [Google Scholar]
  36. Xu Q., Alldus G., Macdonald R., Wilkinson D. G., Holder N. Function of the Eph-related kinase rtk1 in patterning of the zebrafish forebrain. Nature. 1996 May 23;381(6580):319–322. doi: 10.1038/381319a0. [DOI] [PubMed] [Google Scholar]

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