USE OF RETROVIRAL VECTORS TO STUDY NEURAL PLASTICITY

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To elucidate mechanisms which direct development of the mammalian nervous system, retroviral vectors are used to insert heritable genetic markers and modifiers into primordial neural tissue. In the course of these studies, phenomena were observed which hint at an extraordinary degree of plasticity late in development of the immature nervous system. The studies proposed endeavor to determine the pervasiveness of these phenomena and to understan the variables directing this plasticity in order to exploit its potential i the prevention, compensation, and repair of the damaged developing nervous system. Such an understanding may not only lend insight into strategies of normal neural development, but also into development "gone awry"--i.e., unchecked plasticity--which may prove to be a molecular mechanism contributing to neural oncogenesis. Work will continue IN VITRO and IN VIV in the mouse. IN VITRO, "immortalizing" genes are inserted into individual neural stem cells--both of neural tube (cerebellum) and neural crest origin--allowing, through the creation of neural cell lines, a study of the r subsequent differentiation and commitment. In cerebellum, lines from ostensibly different neural cell types appear not only to be clonally-related, but to display plasticity in the expression of their phenotype. Work in this system will seek to determine the factors which direct differentiation down a given phenotypic path or allow a selected phenotype to change, and to use these lines for neural transplantation. Lines from neural crest will be similarly characterized, searched for late vs early commitment, assessed for degrees of plasticity, and serving as transplantation material. IN VIVO, through microinjection of vectors containing "marker" genes into neonatal and embryonic mouse CEREBELLUM and embryonic mouse RETINA, individual progenitor cells have been labeled in si u allowing lineage mapping. Two conclusions are emerging: (a) multiple neura cell types are present in a given clone, suggesting that they share a commo progenitor with divergence as late as the last cell division (retina); (b) multipotent progenitors in the CNS may migrate with commitment to cell type occurring only later, following interaction with its microenvironment (postnatal cerebellum). Lineage patterns in pre- and postnatal cerebellum will be analyzed to validate these impressions and provide a basis for transplantation experiments.