CDC-25.1 stability is regulated by distinct domains to restrict cell division during embryogenesis in C. elegans.
Cdc25 phosphatases are key positive cell cycle regulators that coordinate cell divisions with growth and morphogenesis in many organisms. Intriguingly in C. elegans, two cdc-25.1(gf) mutations induce tissue-specific and temporally restricted hyperplasia in the embryonic intestinal lineage, despite stabilization of the mutant CDC-25.1 protein in every blastomere. We investigated the molecular basis underlying the CDC-25.1(gf) stabilization and its associated tissue-specific phenotype. We found that both mutations affect a canonical beta-TrCP phosphodegron motif, while the F-box protein LIN-23, the beta-TrCP orthologue, is required for the timely degradation of CDC-25.1. Accordingly, depletion of lin-23 in wild-type embryos stabilizes CDC-25.1 and triggers intestinal hyperplasia, which is, at least in part, cdc-25.1 dependent. lin-23(RNAi) causes embryonic lethality owing to cell fate transformations that convert blastomeres to an intestinal fate, sensitizing them to increased levels of CDC-25.1. Our characterization of a novel destabilizing cdc-25.1(lf) intragenic suppressor that acts independently of lin-23 indicates that additional cues impinge on different motifs of the CDC-25.1 phosphatase during early embryogenesis to control its stability and turnover, in order to ensure the timely divisions of intestinal cells and coordinate them with the formation of the developing gut.
Hebeisen
Michaël
M
Department of Biology, McGill University, Montreal, Quebec, H3A 1B1, Canada.
Roy
Richard
R
D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D017173:Caenorhabditis elegans / Q000166:cytology / Q000196:embryology* / Q000235:genetics*; D029742:Caenorhabditis elegans Proteins / Q000235:genetics; D002453:Cell Cycle; D018797:Cell Cycle Proteins / Q000235:genetics; D002455:Cell Division; D019070:Cell Lineage; D004625:Embryo, Nonmammalian; D047108:Embryonic Development; D044783:F-Box Proteins / Q000235:genetics; D018507:Gene Expression Regulation, Developmental; D049452:Green Fluorescent Proteins / Q000378:metabolism; D007413:Intestinal Mucosa / Q000378:metabolism; D007422:Intestines / Q000166:cytology; D008969:Molecular Sequence Data; D009154:Mutation; D017434:Protein Structure, Tertiary; D034622:RNA Interference; D018510:RNA, Helminth / Q000235:genetics; D019076:Transgenes; D020687:cdc25 Phosphatases / Q000235:genetics*
D029742:Caenorhabditis elegans Proteins; D018797:Cell Cycle Proteins; D044783:F-Box Proteins; D018510:RNA, Helminth; C418507:lin-23 protein, C elegans; D049452:Green Fluorescent Proteins; D020687:cdc25 Phosphatases