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Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway

During periods of energetic stress, Caenorhabditis elegans can execute a developmentally quiescent stage called “dauer”, during which all germline stem cells undergo a G2 cell cycle arrest. In animals that lack AMP-activated protein kinase (AMPK) signalling, the germ cells fail to arrest, undergo un...

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Autores principales: Wong, Christopher, Kadekar, Pratik, Jurczak, Elena, Roy, Richard
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132661/
https://www.ncbi.nlm.nih.gov/pubmed/37058536
http://dx.doi.org/10.1371/journal.pgen.1010716
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author Wong, Christopher
Kadekar, Pratik
Jurczak, Elena
Roy, Richard
author_facet Wong, Christopher
Kadekar, Pratik
Jurczak, Elena
Roy, Richard
author_sort Wong, Christopher
collection PubMed
description During periods of energetic stress, Caenorhabditis elegans can execute a developmentally quiescent stage called “dauer”, during which all germline stem cells undergo a G2 cell cycle arrest. In animals that lack AMP-activated protein kinase (AMPK) signalling, the germ cells fail to arrest, undergo uncontrolled proliferation, and lose their reproductive capacity upon recovery from this quiescent stage. These germline defects are accompanied by, and likely result from, an altered chromatin landscape and gene expression program. Through genetic analysis we identified an allele of tbc-7, a predicted RabGAP protein that functions in the neurons, which when compromised, suppresses the germline hyperplasia in the dauer larvae, as well as the post-dauer sterility and somatic defects characteristic of AMPK mutants. This mutation also corrects the abundance and aberrant distribution of transcriptionally activating and repressive chromatin marks in animals that otherwise lack all AMPK signalling. We identified RAB-7 as one of the potential RAB proteins that is modulated by tbc-7 and show that the activity of RAB-7 is critical for the maintenance of germ cell integrity during the dauer stage. We reveal that TBC-7 is regulated by AMPK through two mechanisms when the animals enter the dauer stage. Acutely, the AMPK-mediated phosphorylation of TBC-7 reduces its activity, potentially by autoinhibition, thereby preventing the inactivation of RAB-7. In the more long term, AMPK regulates the miRNAs mir-1 and mir-44 to attenuate tbc-7 expression. Consistent with this, animals lacking mir-1 and mir-44 are post-dauer sterile, phenocopying the germline defects of AMPK mutants. Altogether, we have uncovered an AMPK-dependent and microRNA-regulated cellular trafficking pathway that is initiated in the neurons, and is critical to control germline gene expression cell non-autonomously in response to adverse environmental conditions.
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spelling pubmed-101326612023-04-27 Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway Wong, Christopher Kadekar, Pratik Jurczak, Elena Roy, Richard PLoS Genet Research Article During periods of energetic stress, Caenorhabditis elegans can execute a developmentally quiescent stage called “dauer”, during which all germline stem cells undergo a G2 cell cycle arrest. In animals that lack AMP-activated protein kinase (AMPK) signalling, the germ cells fail to arrest, undergo uncontrolled proliferation, and lose their reproductive capacity upon recovery from this quiescent stage. These germline defects are accompanied by, and likely result from, an altered chromatin landscape and gene expression program. Through genetic analysis we identified an allele of tbc-7, a predicted RabGAP protein that functions in the neurons, which when compromised, suppresses the germline hyperplasia in the dauer larvae, as well as the post-dauer sterility and somatic defects characteristic of AMPK mutants. This mutation also corrects the abundance and aberrant distribution of transcriptionally activating and repressive chromatin marks in animals that otherwise lack all AMPK signalling. We identified RAB-7 as one of the potential RAB proteins that is modulated by tbc-7 and show that the activity of RAB-7 is critical for the maintenance of germ cell integrity during the dauer stage. We reveal that TBC-7 is regulated by AMPK through two mechanisms when the animals enter the dauer stage. Acutely, the AMPK-mediated phosphorylation of TBC-7 reduces its activity, potentially by autoinhibition, thereby preventing the inactivation of RAB-7. In the more long term, AMPK regulates the miRNAs mir-1 and mir-44 to attenuate tbc-7 expression. Consistent with this, animals lacking mir-1 and mir-44 are post-dauer sterile, phenocopying the germline defects of AMPK mutants. Altogether, we have uncovered an AMPK-dependent and microRNA-regulated cellular trafficking pathway that is initiated in the neurons, and is critical to control germline gene expression cell non-autonomously in response to adverse environmental conditions. Public Library of Science 2023-04-14 /pmc/articles/PMC10132661/ /pubmed/37058536 http://dx.doi.org/10.1371/journal.pgen.1010716 Text en © 2023 Wong et al https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Wong, Christopher
Kadekar, Pratik
Jurczak, Elena
Roy, Richard
Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway
title Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway
title_full Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway
title_fullStr Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway
title_full_unstemmed Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway
title_short Germline stem cell integrity and quiescence are controlled by an AMPK-dependent neuronal trafficking pathway
title_sort germline stem cell integrity and quiescence are controlled by an ampk-dependent neuronal trafficking pathway
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10132661/
https://www.ncbi.nlm.nih.gov/pubmed/37058536
http://dx.doi.org/10.1371/journal.pgen.1010716
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