Molecular mechanisms underlying cell-fate determination during organ development.

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Neurons, astrocytes, and oligodendrocytes, i.e., the three major cell types in the brain, differentiate from neural stem cells during development. In the developing brain, neural stem cells are known to reside in the neuroepithelium. It has been suggested that differentiation of these three cell types from the neural stem cells is regulated by cell-external cues as well as cell-intrinsic programs. We have shown that BMP2 inhibits neuronal differentiation and that BMP2 induces expression of negative regulatory helix-loop-helix (HLH) proteins such as Hes5, Id1 and Id3, leading to inhibition of transcriptional activity of neurogenic basic-HLH transcription factors such as neurogenin. We have found that an oligodendrocytic differentiation-inducing transcription factor, Olig2, inhibits the activity of an astrocytic differentiation-inducing transcription factor, STAT3. Taken together with a report by another group that neurogenin inhibits astrocytic differentiation by inhibiting complex form … More ation of STAT3, Smad1 and p300, our findings suggest that the cell-fate in the developing brain is determined in part by cross-inhibitory interactions among transcriptional activation signals. In the fate determination of mouse neuroepithelial cells, Notch signaling plays a role in keeping the progenitors from differentiating into neurons. BMP is also known to inhibit neuronal differentiation. We have shown that BMP2 enhances Notch-induced transcriptional activation of Hes-5 in mouse neuroepithelial cells. Recruitment of p300 to the nuclear protein complex containing the intracellular domain of Notch was facilitated by activated Smad1, which is suggested to contribute to BMIP2-mediated enhancement of Notch-induced Hes-5 expression. These data suggest a novel functional cooperation between Notch signaling and BMP signaling. In conclusion, cross-regulatory interactions among transcriptional regulatory signals are important for the cell-fate determination in the developing central nervous system. Less