p75NTR Regulates Oligodendrocyte Progenitor Development in the SubventricularZone of Postnatal Rats

Summary Generating the appropriate numbers of cells in a particular lineage is critical for normal development of the brain. Progenitor cells of both neuronal and glial lineages are present in the postnatal subventricular zone (SVZ) of rats, with a period of gliogenesis that is maximal during the first two postnatal weeks. We find that the p75 neurotrophin receptor (p75NTR) is abundantly expressed in intermediate progenitor cells in the rat SVZ. Deletion of this receptor elicits an overproduction of oligodendrocyte lineage cells and precocious maturation of these cells with abnormal myelin development during the early stages of myelination, suggesting that p75NTR normally acts to restrict premature differentiation of oligodendrocyte lineage cells. This expression of p75NTR in the SVZ has been observed in rat and human, but not mouse, and we suggest that this may be a mechanism that evolved to regulate the timing and balance between generating cells of a particular lineage while maintaining a pool of progenitor cells in an immature state. We will create a cell-specific rat line to delete p75NTR (p75NTRfl/fl) specifically in oligodendrocyte progenitors (PDGFRa-CreERT2), and use this line as well as the global p75NTR KO rats to investigate mechanisms by which p75NTR regulates oligodendrocyte differentiation and maturation. Additionally, we will determine whether deletion of p75NTR impacts the persistence of the oligodendrocyte progenitor pool in the SVZ. We will assess whether the altered regulation of oligodendrocyte progenitors during development in the p75NTR KO rats impacts the ability to remyelinate after a demyelinating lesion in adult rats.