Signaling mechanisms that govern the switch from neuronal to astrocyte differentiation in neocortical progenitors

As the brain grows during development, progenitor cells generate neurons first, and then switch to producing glial cells. Glia vastly outnumber neurons in the human brain, and consist of two cell types, astrocytes and oligodendrocytes. Progenitor cells demonstrate an intrinsic capacity to give rise to neurons, and must receive extrinsic signals for the induction of astrocytes. We have identified extracellular factors and the relevant intracellular signaling molecules responsible for inducing astrocyte differentiation in cortical progenitor cells. In addition, we have identified a molecular basis for the developmental switch in cortical progenitors from neuron to astrocyte generation.; Two distinct signaling pathways were found to dramatically induce astrocyte differentiation. Cortical progenitor cells from the embryonic rat brain respond to ciliary neurotrophic factor (CNTF) treatment with both astrocyte differentiation and the inhibition of neuronal production. CNTF induces astrocyte differentiation by specifically activating the downstream signaling molecules STAT1 and STAT3, which then induce the direct transcriptional up-regulation of astrocyte-specific gene expression.; Bone morphogenetic proteins (BMPs) are as effective as CNTF at inducing robust astrocyte differentiation of cortical progenitors. The effects of BMP are mediated by BMP receptor activation of Smad1. Together, BMP and CNTF treatment results in virtually all of the progenitor cells becoming astrocytes, with a synergistic activation of astrocyte-specific cell differentiation markers. In addition, both BMP and CNTF induce progenitor cells to withdraw from the cell cycle, by the transcriptional up-regulation of the cell kinase inhibitor p21. The expression of p21 appears to promote further astrocyte differentiation, as p21 knockout cells display a defect in astrocyte differentiation.; The neuronal-specifying transcription factor, neurogenin was found to actively block astrocyte differentiation by sequestering Smad1 and blocking STAT phosphorylation. The downregulation of neurogenin expression appears to be necessary for the switch to astrocyte generation to take place.; We have identified three molecular pathways that have profound effects on progenitor cell differentiation. An understanding how distinct differentiation factors interact to coordinately regulate the induction of alternate cell fates may shed new insights into the timing of critical cell fate decisions during in vivo development and may aid in the future manipulation of neural stem cell differentiation.