Reference - Detail
|Author||Kadekar P, Chaouni R, Clark E, Kazanets A, Roy R.|
|Title||Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence.|
BACKGROUND:Caenorhabditis elegans can endure long periods of environmental stress by altering their development to execute a quiescent state called "dauer". Previous work has implicated LKB1 - the causative gene in the autosomal dominant, cancer pre-disposing disease called Peutz-Jeghers Syndrome (PJS), and its downstream target AMPK, in the establishment of germline stem cell (GSC) quiescence during the dauer stage. Loss of function mutations in both LKB1/par-4 and AMPK/aak(0) result in untimely GSC proliferation during the onset of the dauer stage, although the molecular mechanism through which these factors regulate quiescence remains unclear. Curiously, the hyperplasia observed in par-4 mutants is more severe than AMPK-compromised dauer larvae, suggesting that par-4 has alternative downstream targets in addition to AMPK to regulate germline quiescence.
RESULTS:We conducted three genome-wide RNAi screens to identify potential downstream targets of the protein kinases PAR-4 and AMPK that mediate dauer-dependent GSC quiescence. First, we screened to identify genes that phenocopy the par-4-dependent hyperplasia when compromised by RNAi. Two additional RNAi screens were performed to identify genes that suppressed the germline hyperplasia in par-4 and aak(0) dauer larvae, respectively. Interestingly, a subset of the candidates we identified are involved in the regulation of cell polarity and cytoskeletal function downstream of par-4, in an AMPK-independent manner. Moreover, we show that par-4 temporally regulates actin cytoskeletal organization within the dauer germ line at the rachis-adjacent membrane, in an AMPK-independent manner.
CONCLUSION:Our data suggest that the regulation of the cytoskeleton and cell polarity may contribute significantly to the tumour suppressor function of LKB1/par-4.
|MeSH||AMP-Activated Protein Kinase Kinases Actin Cytoskeleton / ultrastructure* Animals Caenorhabditis elegans / cytology Caenorhabditis elegans / genetics Caenorhabditis elegans / growth & development Caenorhabditis elegans / ultrastructure Caenorhabditis elegans Proteins / genetics* Cell Polarity / genetics Cytoskeleton Genome Germ Cells / cytology* Germ Cells / ultrastructure Hyperplasia Larva / cytology Larva / genetics Larva / ultrastructure Mutation Protein Kinases / genetics Protein Serine-Threonine Kinases / genetics* RNA Interference Stem Cells / cytology*|