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.
