A Complex Regulatory Network Coordinating Cell Cycles During C. elegans Development Is Revealed by a Genome-Wide RNAi Screen

摘要

The development and homeostasis of multicellular animals requires precise coordination of cell division and differentiation. We performed a genome-wide RNA interference screen in Caenorhabditis elegans to reveal the components of a regulatory network that promotes developmentally programmed cell-cycle quiescence. The 107 identified genes are predicted to constitute regulatory networks that are conserved among higher animals because almost half of the genes are represented by clear human orthologs. Using a series of mutant backgrounds to assess their genetic activities, the RNA interference clones displaying similar properties were clustered to establish potential regulatory relationships within the network. This approach uncovered four distinct genetic pathways controlling cell-cycle entry during intestinal organogenesis. The enhanced phenotypes observed for animals carrying compound mutations attest to the collaboration between distinct mechanisms to ensure strict developmental regulation of cell cycles. Moreover, we characterized [ubc-25][1] , a gene encoding an E2 ubiquitin-conjugating enzyme whose human ortholog, UBE2Q2, is deregulated in several cancers. Our genetic analyses suggested that [ubc-25][1] acts in a linear pathway with [cul-1][2] /Cul1, in parallel to pathways employing [cki-1][3] /p27 and [lin-35][4] /pRb to promote cell-cycle quiescence. Further investigation of the potential regulatory mechanism demonstrated that [ubc-25][1] activity negatively regulates [CYE-1][5]/cyclin E protein abundance in vivo . Together, our results show that the [ubc-25][1] -mediated pathway acts within a complex network that integrates the actions of multiple molecular mechanisms to control cell cycles during development. [1]: http://www.wormbase.org/db/get?name=ubc-25;class=Gene [2]: http://www.wormbase.org/db/get?name=cul-1;class=Gene [3]: http://www.wormbase.org/db/get?name=cki-1;class=Gene [4]: http://www.wormbase.org/db/get?name=lin-35;class=Gene [5]: http://www.wormbase.org/db/get?name=CYE-1;class=Gene.