Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence
Abstract 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 Sy...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2018-06-01
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| Series: | BMC Genomics |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12864-018-4847-y |
| _version_ | 1819238281449046016 |
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| author | Pratik Kadekar Rita Chaouni Emily Clark Anna Kazanets Richard Roy |
| author_facet | Pratik Kadekar Rita Chaouni Emily Clark Anna Kazanets Richard Roy |
| author_sort | Pratik Kadekar |
| collection | DOAJ |
| description | Abstract 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. |
| first_indexed | 2024-12-23T13:33:44Z |
| format | Article |
| id | doaj.art-387d7bda3b7d49f68c4c0c127466fa49 |
| institution | Directory Open Access Journal |
| issn | 1471-2164 |
| language | English |
| last_indexed | 2024-12-23T13:33:44Z |
| publishDate | 2018-06-01 |
| publisher | BMC |
| record_format | Article |
| series | BMC Genomics |
| spelling | doaj.art-387d7bda3b7d49f68c4c0c127466fa492022-12-21T17:45:05ZengBMCBMC Genomics1471-21642018-06-0119111910.1186/s12864-018-4847-yGenome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescencePratik Kadekar0Rita Chaouni1Emily Clark2Anna Kazanets3Richard Roy4Department of Biology, McGill UniversityDepartment of Biology, McGill UniversityDepartment of Biology, McGill UniversityDepartment of Biology, McGill UniversityDepartment of Biology, McGill UniversityAbstract 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.http://link.springer.com/article/10.1186/s12864-018-4847-yPAR-4AMPKActin cytoskeletonPeutz-Jeghers SyndromeDauerGerm line |
| spellingShingle | Pratik Kadekar Rita Chaouni Emily Clark Anna Kazanets Richard Roy Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence BMC Genomics PAR-4 AMPK Actin cytoskeleton Peutz-Jeghers Syndrome Dauer Germ line |
| title | Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence |
| title_full | Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence |
| title_fullStr | Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence |
| title_full_unstemmed | Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence |
| title_short | Genome-wide surveys reveal polarity and cytoskeletal regulators mediate LKB1-associated germline stem cell quiescence |
| title_sort | genome wide surveys reveal polarity and cytoskeletal regulators mediate lkb1 associated germline stem cell quiescence |
| topic | PAR-4 AMPK Actin cytoskeleton Peutz-Jeghers Syndrome Dauer Germ line |
| url | http://link.springer.com/article/10.1186/s12864-018-4847-y |
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