| During the development of the CNS, the regulation of cell differentiation is tightly imposed to insure the correct differentiation of neurons and glia cells. Multiple extracellular factors and intrinsic transcription factors are required for regulating various processes during development; not surprisingly, one common factor can trigger multiple signaling pathways and also serve different functions in different cell-context environment. In the case of CNS development, our lab has reported the JAK-STAT signaling induced by LIF is the major machinery for astrocyte fate determination but is suppressed by neurogenic factors during the early neurogenic stages. However, the molecular mechanisms are just beginning to be elucidated.;My research work with Dr. Yi Sun is to establish methods to maintain the neurogenic potential of neural stem cells through understanding the molecular mechanism of the proneural basic-Helix-Loop-Helix (bHLH) transcription factor Neurogenin1 (Ngn1), which initiates neuronal fate determination of the neural stem cells. Through the combination of genome-wide location analysis (ChIP-on-chip) and gene expression microarray, we have found novel targets of Ngn1. Besides its neurogenic function, our current results reveal that Ngn1 inhibit gliogenesis through multiple mechanisms. Not only by direct transcriptional repression of GFAP, the marker protein for astrocytes, and Olig1, one of the transcription factors for oligodendrogliogenesis; Ngn1 also post-transcriptionally represses components of JAK-STAT signaling pathway via upregulating a brain-specific microRNA, miR-9 s expression. Furthermore, we found one of the potent astrogliogenic extracellular factors, LIF, promotes the neurogenesis instead of gliogenesis when Ngn1 is in presence. Further biochemistry experiments indicate that LIF enhances the association between Ngn1 and its transcriptional coactivator CBP/p300 to activate neuronal differentiation gene transcription, whereas PLCgamma-PKC signaling inhibitors abolish this enhancement of association. In total, our findings suggest that cell intrinsic properties, i.e. pro-neural transcription factors play major roles in cell lineage determination in the course of CNS development at multiple levels to ensure neural progenitors adopt the neuronal cell fate. |
