Although stem cell therapy has been proposed for repair, still relatively little is known about the behavior of these cells in the adult injured CNS. It is well accepted that two major mitogens for adult SVZ cells have very different effects on their behavior: FGF2 increases proliferation and favors neurogenesis (Kuhn et al., 1997), while EGF increases proliferation at the expenses of neurogenesis (Doetsch et al., 2002), but the downstream signaling pathways remain elusive. This proposal tests the hypothesis that p27Kip1 and p53, two crucial cell cycle regulators which are expressed in the adult SVZ and often mutated in glioblastomas, are downstream effectors of signaling pathways activated by FGF2 and EGF in SVZ cells. This hypothesis is based on genetic evidence derived from the phenotypic characterization of p27Kip1-/- and in p53-/- mice, conducted in our laboratory and indicating a close similarity between the phenotype of p53-/- mice and FGF2 injection, and that of p27Kip1-/- mice and EGF injection. We further propose, based on the results of our proteomic and gene profiling studies, a molecular mechanism integrating these two cell cycle genes within downstream signaling networks that modulate lineage determination and survival. Therefore, this proposal addresses novel molecular mechanisms for the role of the cell cycle molecules p27Kip1 and p53 in modulating not only proliferation, but also survival and lineage specification of adult progenitors and neural stem cells residing in the adult subventricular zone (SVZ).
Specific aim 1 tests the hypothesis that cell cycle regulation of slow and fast-proliferating cells in the adult SVZ is differentially modulated by p27Kip1 and p53 and that these molecules are downstream of FGF2 and EGF.
Specific aim 2 tests the hypothesis that the opposing role of FGF2 and EGF on adult neurogenesis is dependent on their effect on p53 and p27Kip1 which play antagonistic roles on molecular networks affecting cell fate determination.
Specific aim 3 will test the hypothesis that p53 and p27Kip1 exert antagonistic functions on apoptotic pathways in adult SVZ cells. The results of the proposed studies will significantly extend our current knowledge on the mechanisms of cell division and neoplastic transformation of adult SVZ cells. In addition, by addressing novel and unexplored roles for p27Kip and p53 as part of transcriptional networks and signaling pathways, they will also significantly impact several other fields, including developmental neurobiology and clinical neurobiology.
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