LAUSR

Stem cell proliferation and cellular differentiation need to be tightly coordinated with the mitotic cell cycle. But how is this done at the mechanistic level? How do gene regulatory proteins, such as pluripotency factors and lineage-specific transcription factors, interact with the cell cycle machinery either to maintain stemness or to promote differentiation? And to what extent are the cell cycle proteins taking an active role in these developmental processes? This is by and large not known. The cell cycle has often been regarded as an independent self-perpetuating process, with the core cell cycle proteins controlling the progression from one cell cycle phase to the next in a relatively stereotypic manner. Growing evidence indicates, however, that close cross-talk between the cell cycle machinery and the regulatory transcription factor network may play a more profound role than previously anticipated.[1] In this issue of BioEssays, Muhr and Hagey[2] present the hypothesis that the choice between stem cell maintenance and differentiation relies on direct interactions and reciprocal regulation between the cell cycle machinery and differentiation factors. It is further hypothesized that these pathways have co-evolved and are rooted in the diversification of cell cycle proteins and transcription factors during evolution. To back-up this hypothesis, the authors compared the repertoire of cell cycle factors, such as cyclins and cyclindependent kinases (CDKs), and differentiation factors in representative genomes of four phyla, from single eukaryotic yeast cells to humans. Not too surprisingly, the repertoire of these factors has increased dramatically during evolution. An intriguing observation is, however, that Trichoplax, which represents a basal branch of multicellular organisms with only six cell types, is equipped with a complete catalogue of cyclins, CDKs, and stem cell regulators. Thus the basic setup was there early in evolution, and the authors hypothesize that this may have enabled the diversification of stem cell identities and been a prerequisite for the evolvement of complex animal forms. During early embryonic development cell cycles are generally very rapid, alternating between mitosis (M) and DNA synthesis (S) phases. In mammals, fast cell cycles are characteristic of pluripotency, while cell-lineage restriction is coupled to longer cell cycles, including gap phases, regulatory checkpoints, and cells may also enter quiescence.[1] Weather the cell cycle length is a cause or consequence of pluripotency has not been entirely resolved. As pointed out,[2] both quiescence and differentiation interfere with cell cycle progression and block prolif-