Generating asymmetry: with and without self-renewal.

At some point during the history of organismal evolution, unicellular, unipotent and mitotically active cells acquired an ability to undergo a special type of cell division called asymmetric division. By this special type of cell division, these cells could divide to generate two different progeny or to self-renew and at the same time generate a progeny that is committed to become a cell different from the mother cell. This type of cell division, which forms the basis for the functioning of totipotent or multipotent stem cells, underlies the fundamental basis for the developmental evolution of organisms. It is not clear if the asymmetric division without self-renewal preceded the asymmetric division with self-renewal. It is reasonable to assume that the asymmetric division without self-renewal preceded the asymmetric division with self-renewal. In this review we explore the genetic regulation of these two types of asymmetric divisions using the Drosophila central nervous system (CNS) as a model system. The results from recent studies argue that for cells to undergo a self-renewing asymmetric division, certain "stem cell" proteins must be maintained or up-regulated, while genes encoding proteins responsible for differentiation must be repressed or down-regulated. As long as a balance between these two classes of proteins is maintained via asymmetric segregation and activation/repression, the progeny that receives stem cell proteins/maintains stem cell competence will have the potential to undergo self-renewing asymmetric division. The other progeny will commit to differentiate. In non-self-renewing asymmetric division, down-regulation of stem cell proteins/competence combined with asymmetric segregation of cell identity specifying factors (either cell-autonomous or a combination of cell autonomous and non-cell autonomous signals) cause the two progeny to assume different differentiated identities. Identification of mutations that confer a stem cell type of division to nonstem cell precursors, or mutations that eliminate asymmetric division, has led the way in elucidating the molecular basis for these divisions. Given that there is a considerable degree of conservation of genes and their function, these studies should provide clear insight into how the self-renewing asymmetric division of stem cells in neural and other lineages is regulated not only in Drosophila but also in vertebrates including humans.