The overall objective of this application is to understand the molecular mechanisms by which Notch regulates astroglial differentiation during cortical development. It has been postulated that Notch participates in diverse cell-fate decisions during development primarily as an anti-differentiation signal. Recently, it was proposed that Notch instructs multipotential neural progenitor/stem cells to adopt an astroglial fate. The mechanisms by which Notch promotes astrogliogenesis are unknown. Whether Notch plays a permissive or instructive role for astrogliogenesis has been highly debated. To gain insight into these issues the principal investigator has recently established a cell culture system where robust activation of the astrocyte specific genes GFAP and S100? by Notch was observed. Through promoter analysis, Notch leads to activation of the GFAP and S100? promoters via a CSL (CBF1, Su(H), Lag1)-dependent pathway and potential CSL-independent mechanisms. In addition to Notch signaling, it was previously reported that LIF, through activation of the JAK-STAT pathway, is one of the major astrogliogenic signals in the developing CNS. Recently, another LIF-triggered pathway, the PI3Kinase-AKT pathway, through inhibition of the nuclear co-receptor, N-CoR, is postulated to also activate glial genes. Although Notch potentiates astrocyte differentiation in progenitor cells competent for gliogenesis, it is not sufficient to cause astrogliogenesis in cortical progenitors during the neurogenic period. Are there age-dependent mechanisms involved in activation of the various gliogenic pathways? Why does the CNS use so many pathways to induce astroglial differentiation? Do the different gliogenic pathways cross talk with each other? These are important issues that will be addressed in the proposed study, in which Specific Aim 1 proposes to characterize the mechanisms by which Notch activates the GFAP promoter, and specific Aim 2 proposes to examine the age-dependence and potential crosstalk among different gliogenic pathways. The proposed research will advance our understanding of the cell-context dependence of Notch actions and of various astrogliogenic mechanisms during cortical development, and it will also provide new insights into the regulation of astrocytes and their involvement in the pathogenesis of various developmental and adult neurological disorders. ? ?
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