ECM and the Differentiation/Plasticity of DA Neurons

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DESCRIPTION (provided by the applicant): We have recently shown in animal models of Parkinson's disease, a progressive neurodegenerative disorder characterized by the degeneration of nigrostriatal dopaminergic neurons, that there is a robust proliferative burst of neuroprogenitor cells in response to the loss of dopamine neurons. However, these cells remain in an undifferentiated state. We have also shown that in response to the degeneration of dopamine neurons in the substantia nigra that the remaining un-injured dopamine neurons are able to compensate for the loss by extending collateral axonal fibers. However, this compensatory response becomes greatly attenuated with increasing age. Therefore, based on these previous results we propose further experiments designed to discover how to induce the differentiation of dopaminergic progenitor cells and injury-induced collateral sprouting in animal models of Parkinson's disease. Integrins are cell surface receptors involved in cell-matrix and cell-cell adhesion interactions in salt organs and play an important role in regulating cell proliferation, survival, and process outgrowth. Studies outside the nervous system indicate that an integration of signals derived from both integrin-ECM interactions and soluble growth factors are required for cellular differentiation. Thus, we hypothesize that ECM molecules expressed in the CNS in combination with growth factors act together to induce neural progenitor cell commitment and differentiation. To test our hypothesis, we propose to characterize which ECM molecules are expressed during the time in development when midbrain dopaminergic progenitors are exiting the cell cycle and making their final commitment to the dopaminergic neuronal fate. In parallel, we plan to culture these progenitor cells on different ECM substrates in combination with fibroblast growth factor-2 (FGF-2) and determine whether the fate of these cells is regulated. We further hypothesize that as the brain develops, the expression of ECM molecules required for the differentiation of neural progenitor cells into dopaminergic neurons becomes down-regulated. To test this idea we plan to culture midbrain progenitor cells on tissue slices containing the substantia nigra from either developing or mature animals. Since our overall goal is to be able to induce dopaminergic progenitor cell differentiation in mature animals, we propose to test whether the induced expression of integrins by retroviral expression vector infection of uncommitted progenitors will induce their differentiation. Finally, we plan to test the hypothesis that age-related differences in ECM molecules play a role in supporting or inhibiting collateral sprouting. Thus, we plan to culture embryonic dopamine neurons on striatal tissue slices collected from control and MPTP mice of different age groups.