{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,26]],"date-time":"2026-09-26T00:17:09Z","timestamp":1790381829318,"version":"4.1.0"},"reference-count":53,"publisher":"The Company of Biologists","issue":"20","license":[{"start":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T00:00:00Z","timestamp":1761177600000},"content-version":"vor","delay-in-days":8,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["R01AG065672"],"award-info":[{"award-number":["R01AG065672"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,10,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Declines in tissue renewal and repair due to alterations in tissue stem cells is a hallmark of aging. Many stem cell pools are maintained by morphologically complex niches. Using the C. elegans hermaphrodite germline stem cell system, we analyzed age-related changes in the morphology of the niche, the distal tip cell (DTC), and identified a molecular mechanism that promotes a subset of these changes. We found decreases in the number and length of long DTC processes with age. We also found that a long-lived daf-2 mutant exhibits a daf-16-dependent maintenance of long DTC processes. Surprisingly, the tissue requirement for daf-16(+) is non-autonomous, and daf-16(+) in body wall muscle is both necessary and sufficient. In addition, after a delay, pre-formed DTC processes deteriorate upon premature germline differentiation, but not upon cell cycle inhibition. We propose a reciprocal DTC-germline interaction model and speculate how reduced daf-2 activity both delays stem cell exhaustion and maintains DTC processes. These studies establish the C. elegans DTC as a powerful in vivo model for understanding age-related changes in cellular morphology and their consequences in stem cell systems.<\/jats:p>","DOI":"10.1242\/dev.204970","type":"journal-article","created":{"date-parts":[[2025,10,22]],"date-time":"2025-10-22T12:28:36Z","timestamp":1761136116000},"source":"Crossref","is-referenced-by-count":3,"title":["Non-autonomy of age-related morphological changes in the\n                    <i>C. elegans<\/i>\n                    germline stem cell niche"],"prefix":"10.1242","volume":"152","author":[{"ORCID":"https:\/\/orcid.org\/0009-0009-1865-1569","authenticated-orcid":false,"given":"Nilay","family":"Gupta","sequence":"first","affiliation":[{"name":"New York University 1 Department of Biology , , New York, NY 10003,","place":["USA"]},{"name":"NYU Grossman School of Medicine 2 Department of Cell Biology , , New York, NY 10016,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0006-6065-1376","authenticated-orcid":false,"given":"Mia","family":"Sinks","sequence":"additional","affiliation":[{"name":"NYU Grossman School of Medicine 2 Department of Cell Biology , , New York, NY 10016,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5893-7232","authenticated-orcid":false,"given":"E. Jane Albert","family":"Hubbard","sequence":"additional","affiliation":[{"name":"NYU Grossman School of Medicine 2 Department of Cell Biology , , New York, NY 10016,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,10,23]]},"reference":[{"key":"2025102304554503900_DEV204970C1","doi-asserted-by":"publisher","first-page":"589","DOI":"10.1016\/0092-8674(87)90128-0","article-title":"glp-1 is required in the germ line for regulation of the decision between mitosis and meiosis in C. elegans","volume":"51","author":"Austin","year":"1987","journal-title":"Cell"},{"key":"2025102304554503900_DEV204970C2","doi-asserted-by":"publisher","first-page":"755","DOI":"10.1242\/dev.116.3.755","article-title":"Characterization of a germ-line proliferation mutation in C. elegans","volume":"116","author":"Beanan","year":"1992","journal-title":"Development (Cambridge, England)"},{"key":"2025102304554503900_DEV204970C3","doi-asserted-by":"publisher","first-page":"71","DOI":"10.1093\/genetics\/77.1.71","article-title":"The genetics of Caenorhabditis elegans","volume":"77","author":"Brenner","year":"1974","journal-title":"Genetics"},{"key":"2025102304554503900_DEV204970C4","doi-asserted-by":"publisher","first-page":"45","DOI":"10.1038\/s41580-022-00510-w","article-title":"Ageing and rejuvenation of tissue stem cells and their niches","volume":"24","author":"Brunet","year":"2023","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025102304554503900_DEV204970C5","doi-asserted-by":"publisher","first-page":"e88372","DOI":"10.1371\/journal.pone.0088372","article-title":"A DTC niche plexus surrounds the germline stem cell pool in Caenorhabditis elegans","volume":"9","author":"Byrd","year":"2014","journal-title":"PLoS ONE"},{"key":"2025102304554503900_DEV204970C6","doi-asserted-by":"publisher","first-page":"dev167734","DOI":"10.1242\/dev.167734","article-title":"Soma-germ line interactions and a role for muscle in the regulation of C. elegans sperm motility","volume":"145","author":"Chavez","year":"2018","journal-title":"Development (Cambridge, England)"},{"key":"2025102304554503900_DEV204970C7","doi-asserted-by":"publisher","first-page":"3051","DOI":"10.1091\/mbc.e06-03-0170","article-title":"Cellular analyses of the mitotic region in the Caenorhabditis elegans adult germ line","volume":"17","author":"Crittenden","year":"2006","journal-title":"Mol. Biol. Cell"},{"key":"2025102304554503900_DEV204970C8","doi-asserted-by":"publisher","first-page":"iyac003","DOI":"10.1093\/genetics\/iyac003","article-title":"WormBase in 2022-data, processes, and tools for analyzing Caenorhabditis elegans","volume":"220","author":"Davis","year":"2022","journal-title":"Genetics"},{"key":"2025102304554503900_DEV204970C9","doi-asserted-by":"publisher","first-page":"830","DOI":"10.1126\/science.1074240","article-title":"Timing requirements for insulin\/IGF-1 signaling in C. elegans","volume":"298","author":"Dillin","year":"2002","journal-title":"Science"},{"key":"2025102304554503900_DEV204970C10","doi-asserted-by":"publisher","first-page":"4524","DOI":"10.1091\/mbc.E14-06-1084","article-title":"The cell biology of aging","volume":"26","author":"DiLoreto","year":"2015","journal-title":"Mol. Biol. Cell"},{"key":"2025102304554503900_DEV204970C11","doi-asserted-by":"publisher","first-page":"167","DOI":"10.1534\/genetics.115.178061","article-title":"Analysis of germline stem cell differentiation following loss of GLP-1 notch activity in caenorhabditis elegans","volume":"201","author":"Fox","year":"2015","journal-title":"Genetics"},{"key":"2025102304554503900_DEV204970C12","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1242\/dev.059535","article-title":"Cyclin E and CDK-2 regulate proliferative cell fate and cell cycle progression in the C. elegans germline","volume":"138","author":"Fox","year":"2011","journal-title":"Development (Cambridge, England)"},{"key":"2025102304554503900_DEV204970C13","doi-asserted-by":"publisher","first-page":"dev161042","DOI":"10.1242\/dev.161042","article-title":"GSK-3 promotes S-phase entry and progression in C. elegans germline stem cells to maintain tissue output","volume":"145","author":"Furuta","year":"2018","journal-title":"Development"},{"key":"2025102304554503900_DEV204970C14","doi-asserted-by":"publisher","first-page":"1101","DOI":"10.1093\/genetics\/161.3.1101","article-title":"Genetic analysis of tissue aging in Caenorhabditis elegans: a role for heat-shock factor and bacterial proliferation","volume":"161","author":"Garigan","year":"2002","journal-title":"Genetics"},{"key":"2025102304554503900_DEV204970C15","doi-asserted-by":"publisher","first-page":"823","DOI":"10.1016\/j.cub.2019.01.056","article-title":"Ectopic germ cells can induce niche-like enwrapment by neighboring body wall muscle","volume":"29","author":"Gordon","year":"2019","journal-title":"Curr. Biol."},{"key":"2025102304554503900_DEV204970C16","doi-asserted-by":"publisher","DOI":"10.17912\/micropub.biology.001202","article-title":"A DTC morphometrics package for quantification of complex and variable cellular morphology using ImageJ","volume":"2024","author":"Gupta","year":"2024","journal-title":"MicroPubl Biol."},{"key":"2025102304554503900_DEV204970C17","doi-asserted-by":"publisher","first-page":"101","DOI":"10.1006\/dbio.1999.9356","article-title":"Ultrastructural features of the adult hermaphrodite gonad of Caenorhabditis elegans: relations between the germ line and soma","volume":"212","author":"Hall","year":"1999","journal-title":"Dev. Biol."},{"key":"2025102304554503900_DEV204970C18","doi-asserted-by":"publisher","first-page":"2913","DOI":"10.1242\/dev.120.10.2913","article-title":"lag-2 may encode a signaling ligand for the GLP-1 and LIN-12 receptors of C. elegans","volume":"120","author":"Henderson","year":"1994","journal-title":"Development"},{"key":"2025102304554503900_DEV204970C19","doi-asserted-by":"publisher","first-page":"808","DOI":"10.1038\/nature01135","article-title":"Stochastic and genetic factors influence tissue-specific decline in ageing C. elegans","volume":"419","author":"Herndon","year":"2002","journal-title":"Nature"},{"key":"2025102304554503900_DEV204970C20","doi-asserted-by":"publisher","first-page":"9","DOI":"10.1098\/rstb.2010.0276","article-title":"The first long-lived mutants: discovery of the insulin\/IGF-1 pathway for ageing","volume":"366","author":"Kenyon","year":"2010","journal-title":"Philos. Trans. R. Soc. B Biol. Sci."},{"key":"2025102304554503900_DEV204970C21","doi-asserted-by":"publisher","first-page":"504","DOI":"10.1038\/nature08980","article-title":"The genetics of ageing","volume":"464","author":"Kenyon","year":"2010","journal-title":"Nature"},{"key":"2025102304554503900_DEV204970C22","doi-asserted-by":"publisher","first-page":"461","DOI":"10.1038\/366461a0","article-title":"A C. elegans mutant that lives twice as long as wild type","volume":"366","author":"Kenyon","year":"1993","journal-title":"Nature"},{"key":"2025102304554503900_DEV204970C23","first-page":"29","volume-title":"Germline Stem Cells and Their Regulation in the Nematode Caenorhabditis elegans","author":"Kershner","year":"2013"},{"key":"2025102304554503900_DEV204970C24","doi-asserted-by":"publisher","first-page":"322","DOI":"10.1016\/j.ydbio.2004.12.021","article-title":"Caenorhabditis elegans germline patterning requires coordinated development of the somatic gonadal sheath and the germ line","volume":"279","author":"Killian","year":"2005","journal-title":"Dev. Biol."},{"key":"2025102304554503900_DEV204970C25","doi-asserted-by":"publisher","first-page":"208","DOI":"10.1016\/0012-1606(81)90284-0","article-title":"On the control of germ cell development in Caenorhabditis elegans","volume":"81","author":"Kimble","year":"1981","journal-title":"Dev. Biol."},{"key":"2025102304554503900_DEV204970C26","doi-asserted-by":"publisher","first-page":"942","DOI":"10.1126\/science.277.5328.942","article-title":"daf-2, an insulin receptor-like gene that regulates longevity and diapause in Caenorhabditis elegans","volume":"277","author":"Kimura","year":"1997","journal-title":"Science"},{"key":"2025102304554503900_DEV204970C27","doi-asserted-by":"publisher","first-page":"dev173195","DOI":"10.1242\/dev.173195","article-title":"Rapid population-wide declines in stem cell number and activity during reproductive aging in C. elegans","volume":"146","author":"Kocsisova","year":"2019","journal-title":"Development"},{"key":"2025102304554503900_DEV204970C28","doi-asserted-by":"publisher","first-page":"pgaf220","DOI":"10.1093\/pnasnexus\/pgaf220","article-title":"Notch signaling in germ line stem cells controls reproductive aging in Caenorhabditis elegans","volume":"4","author":"Kocsisova","year":"2025","journal-title":"PNAS Nexus"},{"key":"2025102304554503900_DEV204970C29","doi-asserted-by":"publisher","first-page":"e35428","DOI":"10.1371\/journal.pone.0035428","article-title":"C. elegans rrf-1 mutations maintain RNAi efficiency in the soma in addition to the germline","volume":"7","author":"Kumsta","year":"2012","journal-title":"PLoS ONE"},{"key":"2025102304554503900_DEV204970C30","doi-asserted-by":"publisher","first-page":"e18370","DOI":"10.7554\/eLife.18370","article-title":"C. elegans GLP-1\/Notch activates transcription in a probability gradient across the germline stem cell pool","volume":"5","author":"Lee","year":"2016","journal-title":"eLife"},{"key":"2025102304554503900_DEV204970C31","doi-asserted-by":"publisher","first-page":"489","DOI":"10.1016\/S0092-8674(03)00889-4","article-title":"Tissue-specific activities of C. elegans DAF-16 in the regulation of lifespan","volume":"115","author":"Libina","year":"2003","journal-title":"Cell"},{"key":"2025102304554503900_DEV204970C32","doi-asserted-by":"publisher","first-page":"243","DOI":"10.1016\/j.cell.2022.11.001","article-title":"Hallmarks of aging: an expanding universe","volume":"186","author":"Lopez-Otin","year":"2023","journal-title":"Cell"},{"key":"2025102304554503900_DEV204970C33","doi-asserted-by":"publisher","first-page":"299","DOI":"10.1016\/j.cell.2010.09.013","article-title":"TGF-\u03b2 and insulin signaling regulate reproductive aging via oocyte and germline quality maintenance","volume":"143","author":"Luo","year":"2010","journal-title":"Cell"},{"key":"2025102304554503900_DEV204970C34","doi-asserted-by":"publisher","first-page":"671","DOI":"10.1242\/dev.042523","article-title":"Insulin signaling promotes germline proliferation in C. elegans","volume":"137","author":"Michaelson","year":"2010","journal-title":"Development (Cambridge, England)"},{"key":"2025102304554503900_DEV204970C35","doi-asserted-by":"publisher","first-page":"26","DOI":"10.1186\/s12861-015-0076-7","article-title":"Morphologically defined sub-stages of C. elegans vulval development in the fourth larval stage","volume":"15","author":"Mok","year":"2015","journal-title":"BMC Dev. Biol."},{"key":"2025102304554503900_DEV204970C36","doi-asserted-by":"publisher","first-page":"1","DOI":"10.1895\/wormbook.1.164.1","article-title":"Insulin\/insulin-like growth factor signaling in C. elegans","author":"Murphy","year":"2013","journal-title":"WormBook"},{"key":"2025102304554503900_DEV204970C37","doi-asserted-by":"publisher","first-page":"2223","DOI":"10.1242\/dev.034603","article-title":"MSP and GLP-1\/Notch signaling coordinately regulate actomyosin-dependent cytoplasmic streaming and oocyte growth in C. elegans","volume":"136","author":"Nadarajan","year":"2009","journal-title":"Development (Cambridge, England)"},{"key":"2025102304554503900_DEV204970C53","doi-asserted-by":"publisher","first-page":"115","DOI":"10.1093\/genetics\/163.1.115","article-title":"Genetic analysis of Caenorhabditis elegans glp-1 mutants suggests receptor interaction or competition","volume":"163","author":"Pepper","year":"2003","journal-title":"Genetics"},{"key":"2025102304554503900_DEV204970C38","doi-asserted-by":"publisher","first-page":"7107","DOI":"10.1038\/ncomms8107","article-title":"Non-autonomous DAF-16\/FOXO activity antagonizes age-related loss of C. elegans germline stem\/progenitor cells","volume":"6","author":"Qin","year":"2015","journal-title":"Nat. Commun."},{"key":"2025102304554503900_DEV204970C39","doi-asserted-by":"publisher","first-page":"261","DOI":"10.1016\/j.ydbio.2015.10.031","article-title":"Cell cycle features of C. elegans germline stem\/progenitor cells vary temporally and spatially","volume":"409","author":"Roy","year":"2016","journal-title":"Dev. Biol."},{"key":"2025102304554503900_DEV204970C40","doi-asserted-by":"publisher","first-page":"681","DOI":"10.1038\/nrm2234","article-title":"Endocrine regulation of ageing","volume":"8","author":"Russell","year":"2007","journal-title":"Nat. Rev. Mol. Cell Biol."},{"key":"2025102304554503900_DEV204970C41","doi-asserted-by":"publisher","first-page":"108608","DOI":"10.1016\/j.celrep.2020.108608","article-title":"Tissue-specific DNA repair activity of ERCC-1\/XPF-1","volume":"34","author":"Sabatella","year":"2021","journal-title":"Cell Rep."},{"key":"2025102304554503900_DEV204970C42","doi-asserted-by":"publisher","first-page":"171","DOI":"10.1534\/genetics.166.1.171","article-title":"The sys-1 and sys-3 genes cooperate with Wnt signaling to establish the proximal-distal axis of the Caenorhabditis elegans gonad","volume":"166","author":"Siegfried","year":"2004","journal-title":"Genetics"},{"key":"2025102304554503900_DEV204970C43","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1016\/S0092-8674(01)00576-1","article-title":"On the role of RNA amplification in dsRNA-triggered gene silencing","volume":"107","author":"Sijen","year":"2001","journal-title":"Cell"},{"key":"2025102304554503900_DEV204970C44","doi-asserted-by":"publisher","first-page":"103","DOI":"10.1016\/S0378-1119(00)00579-5","article-title":"Ingestion of bacterially expressed dsRNAs can produce specific and potent genetic interference in Caenorhabditis elegans","volume":"263","author":"Timmons","year":"2001","journal-title":"Gene"},{"key":"2025102304554503900_DEV204970C45","doi-asserted-by":"publisher","first-page":"dev203019","DOI":"10.1242\/dev.203019","article-title":"A role for organ level dynamics in morphogenesis of the C. elegans hermaphrodite distal tip cell","volume":"151","author":"Tolkin","year":"2024","journal-title":"Development"},{"key":"2025102304554503900_DEV204970C46","doi-asserted-by":"publisher","first-page":"102706","DOI":"10.1016\/j.isci.2021.102706","article-title":"Neuronal DAF-16-to-intestinal DAF-16 communication underlies organismal lifespan extension in C. elegans","volume":"24","author":"Uno","year":"2021","journal-title":"iScience"},{"key":"2025102304554503900_DEV204970C47","doi-asserted-by":"publisher","first-page":"bio060261","DOI":"10.1242\/bio.060261","article-title":"Aging disrupts spatiotemporal regulation of germline stem cells and niche integrity","volume":"13","author":"Urman","year":"2024","journal-title":"Biol. Open"},{"key":"2025102304554503900_DEV204970C48","doi-asserted-by":"publisher","first-page":"883","DOI":"10.1242\/dev.128.6.883","article-title":"Hemicentin, a conserved extracellular member of the immunoglobulin superfamily, organizes epithelial and other cell attachments into oriented line-shaped junctions","volume":"128","author":"Vogel","year":"2001","journal-title":"Development (Cambridge, England)"},{"key":"2025102304554503900_DEV204970C49","doi-asserted-by":"publisher","first-page":"2295","DOI":"10.18632\/aging.101914","article-title":"Cell-autonomous and non-autonomous roles of daf-16 in muscle function and mitochondrial capacity in aging C. elegans","volume":"11","author":"Wang","year":"2019","journal-title":"Aging (Albany NY)"},{"key":"2025102304554503900_DEV204970C50","doi-asserted-by":"publisher","first-page":"4374","DOI":"10.1242\/dev.125393","article-title":"The auxin-inducible degradation (AID) system enables versatile conditional protein depletion in C. elegans","volume":"142","author":"Zhang","year":"2015","journal-title":"Development"},{"key":"2025102304554503900_DEV204970C51","doi-asserted-by":"publisher","first-page":"6339","DOI":"10.1038\/s41467-022-33850-4","article-title":"Intestine-specific removal of DAF-2 nearly doubles lifespan in Caenorhabditis elegans with little fitness cost","volume":"13","author":"Zhang","year":"2022","journal-title":"Nat. Commun."},{"key":"2025102304554503900_DEV204970C52","doi-asserted-by":"publisher","first-page":"4904","DOI":"10.1038\/s41467-024-49318-6","article-title":"DOS-3 mediates cell-non-autonomous DAF-16\/FOXO activity in antagonizing age-related loss of C. elegans germline stem\/progenitor cells","volume":"15","author":"Zhang","year":"2024","journal-title":"Nat. Commun."}],"container-title":["Development"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.204970\/3670179\/dev204970.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.204970\/3670210\/dev204970.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.biologists.com\/dev\/article-pdf\/doi\/10.1242\/dev.204970\/3670210\/dev204970.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,23]],"date-time":"2025-10-23T08:55:56Z","timestamp":1761209756000},"score":1,"resource":{"primary":{"URL":"https:\/\/journals.biologists.com\/dev\/article\/152\/20\/dev204970\/369586\/Non-autonomy-of-age-related-morphological-changes"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,10,15]]},"references-count":53,"journal-issue":{"issue":"20","published-print":{"date-parts":[[2025,10,15]]}},"URL":"https:\/\/doi.org\/10.1242\/dev.204970","relation":{},"ISSN":["0950-1991","1477-9129"],"issn-type":[{"value":"0950-1991","type":"print"},{"value":"1477-9129","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,10,15]]},"article-number":"dev204970"}}