Precise regulation of entry into and exit from the cell cycle is important for the development of multicellular organisms. To understand how cells decide to begin a new division cycle, we study the highly orchestrated divisions of the vulval precursor cells (VPCs). In a genetic screen for defects of VPC cell-cycle control, we identified mutations that specifically disrupt cell division, in addition to mutations that caused pleotropic developmental defects. Mutations of the transcription factors
lin-1 and
lin-31 revealed roles in regulating the VPC cell-cycle arrest through the Cip/Kip cell cycle inhibitor,
cki-1. An allele of the
let-19 gene was also isolated in this screen.
let-19 encodes a homolog of the mediator component, TRAP240.
let-19 mutants display pleotropic defects including extra divisions of the VPCs. Since
lin-1,
lin-31 and
let-19 mutants have defects outside of failure to arrest the VPCs, they are likely required for multiple developmental programs. In addition, we identified a recessive mutation,
he118, that caused a highly penetrant extra cell division phenotype which appeared to be restricted to the VPCs. Several lines of evidence suggest that
he118 disrupts a
cki-1 mediated process. First, loss of
cki-1 activity results in extra cell divisions in multiple lineages, including the VPCs. The
he118 extra cell division phenotype is enhanced by loss of lin-35Rb function, reminiscent of the
cki-1(RNAi) phenotype. Moreover, the
he118 phenotype was rescued by
cki-1-expressing transgenes and we observed nonallelic non-complementation between
cki-1(
gk132) and
he118. Finally, the production of extra VPCs in
he118 is dependent on expression of the cyclin genes
cya-1 and
cye-1 since reducing the function of either suppressed the extra VPC divisions. Interestingly, we found that the
he118 mutation introduces a premature termination within the C. elegans
cdc-14 locus. Although
cdc-14 was originally identified as a phosphatase required for mitotic exit in yeast, its function in higher organisms is not as clear. A recent study of C. elegans
cdc-14 using RNAi (Gruneberg et al., 2002) has suggested an essential role in cytokinesis. We have observed that RNAi of
cdc-14 in either N2 or the RNAi-hypersensitive strain
rrf-3 phenocopies the
he118 mutant. Our data suggest that
cdc-14 has a role in cell-cycle exit, possibly by negatively regulating proteins that promote cell-cycle progression following the completion of mitosis.