Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence

• Published in: BMC genomics Vol. 19; no. 1; p. 462
• Main Authors: Kadekar, Pratik, Chaouni, Rita, Clark, Emily, Kazanets, Anna, Roy, Richard
• Format: Journal Article
• Language: English
• Published: England BioMed Central Ltd 15.06.2018; BioMed Central; BMC
• Subjects: Actin; Actin cytoskeleton; Actin Cytoskeleton - ultrastructure; AMPK; Animals; Caenorhabditis elegans; Caenorhabditis elegans - cytology; Caenorhabditis elegans - genetics; Caenorhabditis elegans - growth & development; Caenorhabditis elegans - ultrastructure; Caenorhabditis elegans Proteins - genetics; Cancer; Cell cycle; Cell Polarity - genetics; Cytoskeleton; Dauer; Environmental stress; Extracellular matrix; Gene mutation; Genes; Genome; Genomes; Genomics; Germ Cells - cytology; Germ Cells - ultrastructure; Germ line; Hyperplasia; Insulin; Kinases; Larva - cytology; Larva - genetics; Larva - ultrastructure; Larvae; LKB1 protein; Metabolism; Molecular chains; Mutation; Nematodes; PAR-4; Peutz-Jeghers Syndrome; Physiological aspects; Polarity; Protein kinase; Protein Kinases - genetics; Protein-Serine-Threonine Kinases - genetics; Proteins; Regulators; RNA Interference; RNA-mediated interference; Screens; Stem cells; Stem Cells - cytology; Target recognition; Tumor suppressor genes; Tumors; Worms; C. elegans; Peutz-Jeghers Syndrome; Germ line; AMPK; Dauer; Actin cytoskeleton; PAR-4
• ISSN: 1471-2164; 1471-2164
• DOI: 10.1186/s12864-018-4847-y

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. 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. Our data suggest that the regulation of the cytoskeleton and cell polarity may contribute significantly to the tumour suppressor function of LKB1/par-4.