Cell fate determination regulated by a transcriptional signal network in the developing mouse brain.

Development of the nervous system is governed by multistep processes in which neurons, astrocytes and oligodendrocytes are produced from common neural stem cells. Differentiation of stem cells into these three types of neural cells is directed, in part, by cell-external cues, such as cytokines. We have examined the effects of astrocyte-inducing cytokines, leukemia inhibitory factor (LIF) and bone morphogenetic protein (BMP) 2 on mouse telencephalic neuroepithelial cells. We found that simultaneous treatment of neuroepithelial cells with LIF and BMP2 synergistically induced astrocytic differentiation. The synergistic effect of the two cytokines is brought about by a complex formation composed of downstream transcription factors signal transducer and activator of transcription (STAT) 3 and Smad1, together with the transcriptional coactivator p300. Recent studies also clarified molecular interactions involving basic helix-loop-helix-type transcription factors that promote differentiation of neuronal or oligodendrocytic cell lineages. For instance, in fetal brain, it has been shown that the neurogenic transcription factor Neurogenin1 inhibits formation of a STAT3/p300/ Smad1 complex and that the oligodendrocytic transcription factor OLIG2 does the same. This suggests the presence of mutual negative interaction among the signaling pathways regulating the three neural cell lineages. Furthermore, we have demonstrated the developmental stage-dependent epigenetic regulation of cell type-specific gene promoters. DNA methylation, histone acetylation and modified-DNA binding proteins are thought to be involved in this process. In the present review, we discuss the cross-talk between transcription factors downstream of the cytokine-signaling pathways and their effects on cell fate determination. We also emphasize the importance of epigenetic modification of lineage-specific gene promoters and chromatin structure in transcription factor-mediated cell fate regulation.