The protein- tyrosine kinase (PTK) family of receptors plays a central role in the development, differentiation and survival of neural cells. This role has been underscored by the finding that a protein-tyrosine kinase of previously unknown function, trk, serves as a receptor for nerve growth factor (NGF), and that the trk- related molecules, trkB and trkC serve as receptors for the NGF-related neurotrophins brain-derived neurotrophic factor (BDNF) and neurotrophin-3 (NT- 3). The overall objective of this research program is to understand the function of two novel receptor PTKs, tyro-2 and tyro-3, which we previously identified (Lai and Lemke, 1991).
The first aim i s to demonstrate that our cDNA isolates of tyro-2 and tyro-3 encode proteins that exhibit protein-tyrosine kinase activity.
The second aim i s to identify their sites of expression in both the developing and mature nervous system. This analysis will reveal if they are expressed in a manner similar to that of molecules of known function. In this regard, the preliminary description has led to the hypothesis that tyro-2 and the neurotransmitter gamma-amino butyric (GABA) are co-expressed in certain neuronal subsets. Confirmation of this hypothesis, which we will directly test in specific aim 2, may have important consequences for certain psychiatric disorders including epilepsy and schizophrenia where disruptions in GABAergic transmission have been observed.
Specific aim 4 tests the hypothesis that one or several members of the neu differentiation factor (NDF)/glial growth factor (GGF) family of molecules, a family of EGF-related molecules, may serve as ligands for tyro-2. The ability of these factors to activate tyro-2 would suggest a critical role in myelination and synapse formation in the peripheral nervous system with considerable implications for peripheral nerve regeneration.
