The mechanisms by which neural stem cells give rise to neurons, astrocytes, or oligodendrocytes are beginning to be elucidated. However, it is not known how the specification of one cell lineage results in the suppression of alternative fates. We find that in addition to inducing neurogenesis, the bHLH transcription factor neurogenin (Ngn1) 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.
Bibliographical noteFunding Information:
We thank Qiufu Ma for providing us with the neurogenin1 construct, and for his many insightful discussions. Many thanks to Zuohua Zhang and Linda Hu for their support and technical advice with the neurogenin antibody. We thank Anne West, Janine Zieg, Qiufu Ma, David Anderson, and Gord Fishell for their critical reading of the manuscript and Adam Shaywitz for his helpful advice regarding p300/CBP. We also acknowledge Drs. D. Anderson, M. Rosenfeld, X. He, M. J. Tsai, I. Rozovsky, M. Whitman, J. Massagué, A. Lassar, R. Eckner, D. Livingston, F. Mariani, and R. Harland for providing critical reagents for our studies. Y. S. has been supported by both the Medical Foundation/Charles H. Hood Foundation and an NIH N.R.S.A. grant during the course of the study; M. N. V. is a Quan Fellow. This research has been supported by an NIH RO1 grant (CA43855) to M. E. G. and MRRC grant (NIHP30-HD 18655).