During the development of the nervous system, a number of cellular processes which include cell proliferation, cell differentiation, cell adhesion, cell migration and cell death are required for the correct formation of neural structures and to obtain functional and reproducible connectivity between them. In the nervous system some of these cellular processes have been shown to be mediated or modulated by growth factors and their receptors. The receptors transduce responses upon activation its ligand through their tyrosine kinase domain the cytoplasmic tail. Examples of such growth factors/receptor pairs are NGF/trk, BDNK/trkB, and NT3/trkC. A yet uncharacterized receptor Tyro-3, belongs to this class and is the subject of our study. The overall goal of this project is to understand some of the functions, primarily in cell adhesion and to identify signal transduction pathways affected by the tyrosine kinas Tyro-3. This receptor has two immunoglobulin-like repeats and two fibronectin type-III repeats in its extracellular portion and intracellularly a functional tyrosine kinase domain, shown to be phosphorylated upon binding of its known ligand gas-6. We will determine the ultrastructural localization of Tyro-3 in the hoppocampus, in order to establish a possible role of Tyro-3 in synaptogenesis and synaptic plasticity. Preliminary data suggests that the Tyro-3 protein and mRNA are preferentially localizd in the dendritic layer of CA1 neurons. This structure has been demonstrated to be crucial for the establishment of short term memory and to be affected in Alzheimers disease. We will also analyze the cell adhesive properties of Tyro-3 and the ability of this adhesion to affect its kinase activity. Cel l adhesion plays a major role in neuronal patterning during development and can affect remodeling of synaptic connections in the adult CNS. We will study the observation that Tyro-3 is phosphorylated upon addition of glutamate to hippocampal neurons in culture. Through these efforts we hope to understand the role of Tyro-3, one of the few nervous ysstem specific tyrosine kinases described so far, and gain insight into the role played by tyrosine kinases in general in the signal transduction events important for the development and functioning of the nervous system.
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