The regulation of cell cycle exit during Caenorhabditis elegans vulva formation

Abstract

Careful coordination of the division, growth and differentiation of cells is important for the development of a multicellular organism. When factors that normally ensure cell cycle exit are disturbed, overproliferation of cells can occur. This can lead to a disruption of the tissue organization, which is characteristic for cancer. In this study, C. elegans was used to research how cell cycle exit is regulated. Using tissue-specific gene knockout in combination with lineage tracing, genes involved in human cancers and the effect of cell cycle inhibitors were investigated in the vulval epithelium of C. elegans. Simultaneous knockout of cep-1, daf-3 and cki-1 led to a significant increase of vulval cells although the loss of cep-1 and daf-3 did not seem to strongly enhance the extra cell division phenotype of cki-1 knockout animals. Furthermore, the effect of loss of HECT-domain ubiquitin ligase UBR-5 was studied. Loss of ubr-5 led to a small population of animals in which the cell cycle was not fully arrested, leading to several extra vulval nuclei. This suggests ubr-5 has a function as an inhibitor of cell cycle exit. Additionally, swsn-8 leads to overproliferation of vulval nuclei. This is in contrast to the inactivation of swsn-1, which predominantly leads to premature cell cycle arrest and only occasionally results in extra cell divisions. A forward genetic screen with swsn-8 mutants showed aberrant vulvae with apparent extra vulval nuclei, which seems promising to further research. In conclusion, this study indicates multiple factors work together to ensure cell divisions are correctly coordinated during development.