ROLES FOR ABL AND ARG IN NEURONAL DEVELOPMENT

Yale University, New Haven CT

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Abstract

The long-term goal of this research is to understand how the Abl and Arg nonreceptor tyrosine kinases regulate the differentiation, morphogenesis, and function of neurons in mice. Our first major aim is to understand how Abl and Arg regulate the organization of actin filaments in cells of the developing neural tube. Abl and Arg are the only nonreceptor tyrosine kinases that contain actin-binding domains, but the precise role of these kinases in regulating the actin cytoskeleton is unclear. We have found that actin filaments are disordered in abl-/-arg-/- neuroepithelial cells. As a consequence, these embryos suffer from serious neural tube defects. We will determine which of the proteins that regulate actin filament formation or localization in neuroepithelial cells mediate control of the actin cytoskeleton by Abl and Arg. Our second major aim is to understand the roles for Abl and Arg in neuronal differentiation and morphogenesis. We have shown that the number of early hindbrain neurons is severely reduced in abl-/-arg-/-embryos, but it is unclear which stages of neuronal development require Abl and Arg. We will determine whether abl- /-arg-/-neuronal precursor cells proliferate, migrate, and differentiate normally. In Drosphila, D-Abl acts within neurons to control axon outgrowth and fasciculation, but it is not known which axon guidance pathways are regulated by D-Abl. We will measure the extension rate of neurites from abl-/-arg-/-neurons on a select group of extracellular matrix molecules to determine which growth cone responses require Abl and Arg. Our third major aim is to understand the function of Arg in the mature brain. Our observations that Arg is concentrated in synapses and the arg-/-mice exhibit behavioral abnormalities suggest that Arg performs an important function in mature neurons. In order to obtain clues to this function, we will first pinpoint the localization of Arg within synapses. Next, we will identify regulators and substrates of Arg in fractioned brain extracts to determine which cellular processes Arg regulates. Finally, following up on a clue to Arg function obtained from behavioral studies, we will perform physiological tests to understand why arg-/-cochlear hair cells do not function properly. The information gained from these studies will allow us to pose sharper mechanistic questions aimed at understanding the biochemistry of signal transduction by Abl and Arg.