Molecular Mechanisms that Regulate Stem Cell Differentiation
Yi Sun
Dept. of Neurology, Children's Hospital and Harvard University, Boston, MA
The mechanisms by which neural stem cells give rise to neurons, astrocytes or oligodendrocytes are beginning to be elucidated. Both environmental cues and cell intrinsic programs act cooperatively in neural stem cell fate specification and differentiation. Cytokines leukemia inhibitory factor (LIF) and cilliary neural trophic factor (CNTF) induce astrocyte differentiation by acting through the signaling receptors gp130 and/or LIFRb. Both LIF and CNTF can activate a number of signaling pathways including the JAK-STAT pathway and the Ras-MAPK pathways. The activation of the JAK-STAT pathway specifically promoted astrocyte differentiation. The transcription factors STAT1 and STAT3 directly bound to and activated the promoter of an astrocyte-specific gene in the CNS, glial fibrillary acidic protein (GFAP). In addition to environmental factors, recently we find that a cell intrinsic bHLH transcription factor neurogenin (Ngn1) promotes neuronal differentiation and simultaneously inhibits the differentiation of neural stem cells into astrocytes. While Ngn1 promotes neurogenesis by functioning as a transcriptional activator, Ngn1 inhibits astrocyte differentiation by sequestering the CBP-Smad1 transcription complex away from astrocyte differentiation genes, and by inhibiting the activation of STAT transcription factors that are necessary for gliogenesis. Thus two distinct mechanisms are involved in the activation and suppression of gene expression during cell-fate specification by neurogenin. Taken together, extracelluair factors as well as intracellular cell fate determination factors are both key elements for controlling the differentiation of neural stem cells.
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