Asymmetric cell division is a process by which a cell divides to produce two different daughter cells. Conceptually, such divisions are an attractive means for stem cells to balance the needs of self-renewal and differentiation during organogenesis and tissue maintenance, by producing one daughter cell that self-renews and another that differentiates. Studies using invertebrates show that intrinsically asymmetric cell divisions are made possible by a complex, but evolutionarily conserved, molecular machinery that polarizes cells and subsequently enables cellfate determinants to be differentially inherited by the two daughter cells, thereby allowing them to adopt different fates. A key determinant of asymmetric cell fates in Drosophila is Numb, a cytoplasmic signaling protein. To examine the importance of asymmetric cell division in mammalian development, we used molecular and genetic approaches to examine the roles played by the mammalian Numb homologues during mouse neurogenesis. Our findings show that the two mouse numb genes, m-numb (Numb) and numblike (Numbl), are functionally redundant and that asymmetric segregation of the Numb proteins and, therefore, asymmetric cell division are essential for stem/progenitor cells to balance self-renewal and differentiation. We further show that stem-cell numbers are strictly controlled in vivo and that tumor suppressors likely play a key role in maintaining stem-cell homeostasis. We also provide evidence that Golgi fragmentation and reconstitution during cell cycle dynamically regulate Numb signaling and represent a novel mechanism for coupling cell-fate determination and cell-cycle progression. We propose that Numb-mediated asymmetric cell division is a mechanism shared by stem cells in many tissues for their progeny to choose between self-renewal and differentiation.
