A 6BETA 1 INTEGRIN-MEDIATED SURVIVAL OF OLIGODENDROCYTES

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DESCRIPTION (Applicant's abstract reproduced verbatim): The following proposed research project is designed to elucidate the role of the alpha6,beta1 integrin in mediating survival of oligodendrocytes using a transgenic approach. Extensive programmed cell death (PCD) is a necessary part of development in the central nervous system (CNS). Understanding the mechanisms that regulate this process is critical for our understanding of normal development and of disease processes involving inappropriate cell death in the CNS, such as multiple sclerosis, Alzheimer's, and Parkinson's. An important function of PCD is to regulate the final number of differentiated neuronal and glial cells in the CNS. Thus, an extensive system involving both positive and negative regulation has developed to ensure that the appropriate numbers of oligodendrocytes are present in order to myelinate and to promote the survival and function of associated neurons. In recent years, many growth factors have been shown to promote survival and differentiation of oligodendrocytes, but it is increasingly clear that these agents act in concert with other mechanisms. Contact with axons, but not soluble factors released by axons, has been shown to prevent oligodendrocytes from entering a default death pathway. Recent work in the ffrench-Constant laboratory has shown that by specifically blocking the interactions of an oligodendrocyte cell surface receptor, the alpha6,beta1 integrin, execution of this survival signal is prevented and cultured oligodendrocytes die. In addition, alpha6,beta1 interactions were shown to dramatically decrease the level of PDGF normally required to induce survival, indicating a synergy between contact-mediated and growth factor-mediated survival cues. These data suggested a hypothesis in which contact between axonal ligands and the alpha6,beta1 integrins is important for oligodendrocyte survival. In the following research plan I outline experiments designed to directly test this hypothesis in vivo, as well as further characterize this interaction using an oligodendrocyte-neuron double culture system.