Transcriptional control of cell-cycle quiescence during C. elegans development

Abstract

During the development of the C. elegans reproductive system, cells that give rise to the vulva, the vulval precursor cells (VPCs), remain quiescent for two larval stages before resuming cell division in the third larval stage. We have identified several transcriptional regulators that contribute to this temporary cell-cycle arrest. Mutation of lin-1 or lin-31, two downstream targets of the Receptor Tyrosine kinase (RTK)/Ras/MAP kinase cascade that controls VPC cell fate, disrupts the temporary VPC quiescence. We found that the LIN-1/Ets and LIN-31/FoxB transcription factors promote expression of CKI-1, a member of the p27 family of cyclin-dependent kinase inhibitors (CKIs). LIN-1 and LIN-31 promote cki-1/Kip-1 transcription prior to their inhibition through RTK/Ras/MAPK activation. Another mutation identified in the screen defined the mdt-13 TRAP240 Mediator subunit. Further analysis of the multi-subunit Mediator complex revealed that a specific subset of its components act in VPC quiescence. These components substantially overlap with the CDK-8 module implicated in transcriptional repression. Taken together, strict control of cell-cycle quiescence during VPC development involves transcriptional induction of CKI-1 and transcriptional regulation through the Mediator complex. These transcriptional regulators represent potential molecular connections between development and the basic cell-cycle machinery.

The Mediator Kinase Module Restrains Epidermal Growth Factor Receptor Signaling and Represses Vulval Cell Fate Specification in Caenorhabditis elegans

“…CKM subunits have been implicated as regulators of canonical Wnt signaling (Zhang and Emmons 2000;Firestein et al 2008;Morris et al 2008) and cell cycle quiescence (Clayton et al 2008), processes which also contribute to vulva development. Activation of Wnt signaling can bypass requirements for let-23/EGFR in vulva development (Gleason et al 2002).…”

“…However, the Muv phenotype of mdt-12/dpy-22 mutants is independent of bar-1/b-catenin (Moghal and Sternberg 2003b), suggesting that the CKM does not repress vulva development through the canonical Wnt signaling pathway. Deregulation of cell cycle quiescence can expand the VPC equivalence group, which are competent to form ectopic vulvae if presented with the appropriate signals [e.g., lin-12/Notch gain of function employed by Clayton et al (2008)]. Although CKM subunits are required for VPC cell cycle quiescence (Clayton et al 2008), this alone is unlikely to account for the ectopic vulvae observed in these animals.…”

“…Deregulation of cell cycle quiescence can expand the VPC equivalence group, which are competent to form ectopic vulvae if presented with the appropriate signals [e.g., lin-12/Notch gain of function employed by Clayton et al (2008)]. Although CKM subunits are required for VPC cell cycle quiescence (Clayton et al 2008), this alone is unlikely to account for the ectopic vulvae observed in these animals. First, the ectopic vulval invaginations observed in cdk-8 and mdt-13/let-19 animals while scoring VPC induction (Table 1) were positioned in the correct location for P3.p, P4.…”

Pygopus activates Wingless target gene transcription through the mediator complex subunits Med12 and Med13

“…Many of its effects have been attributed to the Cdk8 kinase, which phosphorylates the C-terminal domain of Pol II (22,23), the Cyclin H component of the TFIIH general transcription factor (24), and other subunits of the mediator complex (19), as well as specific transcription factors (25)(26)(27)(28)(29). The large Med12 and Med13 proteins are required for specific developmental processes in Drosophila, zebrafish, and Caenorhabditis elegans (30)(31)(32)(33)(34)(35)(36)(37)(38), but their biochemical functions are not understood.…”

The transcription factor FoxB mediates temporal loss of cellular competence for notochord induction in ascidian embryos

“…Previous studies have reported the expression pattern of the FoxB gene in hydra, sea urchin, frog and zebrafish (Cheavalier et al, 2006;Gamse and Sive et al, 2001;Clayton et al, 2008;Tu et al, 2006;Minokawa et al, 2004;Grinblat et al, 1998). In vertebrates, the FoxB gene has been used as a marker gene for hindbrain.…”