Neural progenitor cells in the developing neocortex change over time to produce different neurons, a phenomenon that is also observed in other regions of the nervous system. Mouse Numb (also known as m-numb) and Numbl (also known as numblike or Nbl) are redundant but essential in maintaining virtually all progenitor cells during early neurogenesis. They do this by allowing cells to choose progenitor over neuronal fates. To determine whether their roles change as neurogenesis progresses, we conditionally ablated both genes in the embryonic dorsal forebrain after initial waves of neurogenesis. Here we report that these proteins continue to be required for progenitor-cell maintenance, contrary to recently reported findings. As occurs during early neurogenesis, the loss of Numb and Numbl causes premature progenitor-cell depletion and, consequently, a highly specific malformation of the neocortex and hippocampus. Because progenitor cells can proliferate without Numb and Numbl before neurogenesis, we propose that Numb-mediated asymmetric cell divisions, which diversify many cell fates in Drosophila melanogaster, represent a general mechanism in mammals for stem cells to balance self-renewal and differentiation.
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