Scientific Report 2003-2004 - Cleveland Clinic Lerner Research ...

Our broad research interest is to understandthe molecular and cellular mechanismsthat establish the spatial pattern of thevertebrate nervous system. During developmentof the nervous system, neuronal differentiation,migration, axon guidance, and specificsynaptogenesis take place in a well-organizedmanner.Considering the complexity of the nervoussystem, it is clear that many of the importantmolecules that control neuronal behavior duringdevelopment have not yet been identified. Onefocus of our research is, therefore, to identifynew molecules that are involved in developmentof the nervous system. The approaches include(1) identification of ligands for orphan receptorsand cell adhesion molecules and of receptors forpeptide growth factors, and (2) subtractioncloning and differential library screening.In addition to identifying new molecules,we are interested in understanding how thesemolecules function during development of thenervous system. In particular, we are exploringthe formation of neuronal networks. Function ofthe nervous system is critically dependent uponthe establishment of appropriate connectionsbetween neurons and their target cells. The initialdevelopment of these connections typicallyoccurs before neurons become functionally active,and it is believed to be established by molecularguidance cues. First, axons must follow theircorrect pathway and reach the target region.Second, within the target region, each axon mustfind and recognize the correct target cells andform specific connections. In the vertebratenervous system, this step typically involvestopographic mapping, whereby axons ofneighboring neurons project to neighboring areasin the target region so that the spatial order ofthe projecting neurons is maintained in the target.About half a century ago, Sperry proposed thattopographic mapping could be guided bycomplementary positional labels in gradientsacross pre- and post-synaptic fields. AlthoughSperry’s idea has been widely accepted, molecularThe Department of NeurosciencesMolecular Mechanisms ofVertebrate Neural Developmentidentification of the positional labels has longremained an elusive goal.The Eph receptor family is by far thelargest known family of receptor tyrosine kinasesand contains 14 members in vertebrates. Recently,a family of ligands for the Eph receptors, namedephrins, has been identified, with eight membersthus far cloned in vertebrates. Most of the Ephreceptors and ephrins are predominantlyexpressed in the nervous system, with distinct andoverlapping patterns. Ourprevious work has demonstratedthat ephrin-A2 andits high-affinity receptorEphA3 can act as molecularlabels during the developmentof a topographicprojection. More recentwork by other groups hasrevealed the functions ofthe Eph receptors andephrins in rhombomereformation and neural crestcell migration. Consideringthe large number anddiversity of expressionpatterns, the Eph receptorsand ephrins are likely to playcrucial roles in many aspectsof neural development. Weare further investigating thefunctions of the Ephreceptors and ephrins inspatial patterning ofconnections and cellpositions in the nervoussystem.THE NAKAMOTOLABORATORYRESEARCH FELLOWSMarc Jones, M.S.Hiroshi Matsuoka, M.D., Ph.D.RESEARCH TECHNOLOGISTZhufeng Ouyang, M.D., M.S.RESEARCH TECHNICIANYukari Izutani, B.A.Many congenitaldiseases affect networkMasaru Nakamoto, M.D., Ph.D.formation and cell migrationduring neural development.In addition, the mechanisms of neuronalregeneration after injury is of great clinicalinterest. The study in this field, therefore, willalso produce many important insights in clinicalmedicine.Cheng, H-J., Nakamoto, M., Bergemann, A.D., and Flanagan, J.G. (1995) Complementary gradient in expressionand binding ELF-1 and Mek4 in development of the topographic retinotectal projection map. Cell82:371-381.Nakamoto, M., Cheng, H-J., Friedman, G.C., McLaughlin, T., Hansen, M., O’Leary, D.D.M., and Flanagan,J.G. (1996) Topographically specific effects of ELF-1 on retinal axon guidance in vitro and retinal axonmapping in vivo. Cell 86:755-766.Nakamoto, M. (2000) Eph receptors and ephrins. Int. J. Biochem. Cell Biol. 32:7-12.Nakamoto, M., and A.D. Bergemann (2002) Diverse roles for the Eph family of receptor tyrosine kinasesin carcinogenesis. Microsc. Res. Tech. 59:58-67.Nishida, K., Flanagan, J.G., and M. Nakamoto (2002) Domain-specific olivocerebellar projection regulatedby the EphA-ephrin-A interaction. Development 129:5647-5658.141