Dynamic control of neural stem cells by bHLH factors.

During brain development, neural stem cells change their competency to give sequential rise to neurons and glial cells. Expression of the basic helix-loop-helix (bHLH)-type cell-fate determination factors Ascl1, Olig2, and Hes1 is oscillatory in neural stem cells. Conversely, sustained expression of these factors mediates cell-fate determination. Optogenetic analyses suggest that oscillatory expression regulates maintenance and proliferation of neural stem cells, and that sustained expression induces cell-fate determination. Expression of the Notch ligand Delta-like1 (Dll1), which is controlled by Hes1 and Ascl1, is also oscillatory in neural stem cells. Mathematical modeling showed that if the timing of Dll1 expression is changed, Hes1 oscillations are severely dampened, resulting in impaired maintenance and proliferation of neural stem cells and causing microcephaly. Another bHLH factor, Hes5, also shows oscillatory expression in neural stem cells. Hes5 overexpression and knock-out result in abnormal expression of Hmga1 and Hmga2, which are essential for timing the switching of neural stem-cell competency. These data indicate that oscillatory expression of bHLH factors is important for normal neural stem-cell function in the developing nervous system.