{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,1,7]],"date-time":"2026-01-07T23:16:57Z","timestamp":1767827817191,"version":"3.49.0"},"reference-count":24,"publisher":"Public Library of Science (PLoS)","issue":"1","license":[{"start":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T00:00:00Z","timestamp":1674432000000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000052","name":"NIH Office of the Director","doi-asserted-by":"publisher","award":["OD028242"],"award-info":[{"award-number":["OD028242"]}],"id":[{"id":"10.13039\/100000052","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["www.plosone.org"],"crossmark-restriction":false},"short-container-title":["PLoS ONE"],"abstract":"<jats:p>Much is known about environmental influences on metabolism and systemic insulin levels. Less is known about how those influences are translated into molecular mechanisms regulating insulin production. To better understand the molecular mechanisms we generated marked cells homozygous for a null mutation in the Drosophila TGF-\u03b2 signal transducer <jats:italic>dSmad2<\/jats:italic> in unmated adult females. We then conducted side-by-side single cell comparisons of the pixel intensity of two Drosophila insulin-like peptides (dILP2 and dILP5) in <jats:italic>dSmad2<\/jats:italic><jats:sup><jats:italic>-<\/jats:italic><\/jats:sup> mutant and wild type insulin producing cells (IPCs). The analysis revealed multiple features of <jats:italic>dSmad2<\/jats:italic> regulation of dILPs. In addition, we discovered that dILP5 is expressed and regulated by <jats:italic>dSmad2<\/jats:italic> in circadian pacemaker cells (CPCs). Outcomes of regulation by <jats:italic>dSmad2<\/jats:italic> differ between dILP2 and dILP5 within IPCs and differ for dILP5 between IPCs and CPCs. Modes of <jats:italic>dSmad2<\/jats:italic> regulation differ between dILP2 and dILP5. <jats:italic>dSmad2<\/jats:italic> antagonism of dILP2 in IPCs is robust but <jats:italic>dSmad2<\/jats:italic> regulation of dILP5 in IPCs and CPCs toggles between antagonism and agonism depending upon <jats:italic>dSmad2<\/jats:italic> dosage. Companion studies of dILP2 and dILP5 in the IPCs of <jats:italic>dCORL<\/jats:italic> mutant (<jats:italic>fussel<\/jats:italic> in Flybase and SKOR in mammals) and <jats:italic>upd2<\/jats:italic> mutant unmated adult females showed no significant difference from wild type. Taken together, the data suggest that <jats:italic>dSmad2<\/jats:italic> regulates dILP2 and dILP5 via distinct mechanisms in IPCs (antagonist) and CPCs (agonist) and in unmated adult females that <jats:italic>dSmad2<\/jats:italic> acts independently of <jats:italic>dCORL<\/jats:italic> and <jats:italic>upd2<\/jats:italic>.<\/jats:p>","DOI":"10.1371\/journal.pone.0280529","type":"journal-article","created":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T18:30:12Z","timestamp":1674498612000},"page":"e0280529","update-policy":"https:\/\/doi.org\/10.1371\/journal.pone.corrections_policy","source":"Crossref","is-referenced-by-count":2,"title":["dSmad2 differentially regulates dILP2 and dILP5 in insulin producing and circadian pacemaker cells in unmated adult females"],"prefix":"10.1371","volume":"18","author":[{"given":"Samuel L.","family":"Goldsmith","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1400-7978","authenticated-orcid":true,"given":"Stuart J.","family":"Newfeld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"340","published-online":{"date-parts":[[2023,1,23]]},"reference":[{"key":"pone.0280529.ref001","first-page":"5","article-title":"Dynamics of skeletal muscle-resident stem cells during myogenesis in fibrodysplasia ossificans progressiva","volume":"7","author":"A. Stanley","year":"2022","journal-title":"Regen Med"},{"key":"pone.0280529.ref002","doi-asserted-by":"crossref","first-page":"929","DOI":"10.1016\/j.cell.2005.12.035","article-title":"Emilin1 Links TGF-\u03b2 Maturation to Blood Pressure Homeostasis","volume":"124","author":"L. Zacchigna","year":"2006","journal-title":"Cell"},{"key":"pone.0280529.ref003","doi-asserted-by":"crossref","first-page":"2979","DOI":"10.1534\/g3.118.200572","article-title":"CORL expression and function in Insulin producing neurons reversibly influences adult longevity in Drosophila","volume":"8","author":"N. Tran","year":"2018","journal-title":"G3: Genes, Genomes, Genetics"},{"key":"pone.0280529.ref004","doi-asserted-by":"crossref","first-page":"3392","DOI":"10.1242\/dev.079442","article-title":"Drosophila CORL is required for Smad2-mediated activation of Ecdysone Receptor expression in the mushroom body","volume":"139","author":"N. Takaesu","year":"2012","journal-title":"Development"},{"key":"pone.0280529.ref005","doi-asserted-by":"crossref","first-page":"199","DOI":"10.1016\/j.cmet.2009.08.002","article-title":"Remote control of Insulin secretion by fat cells in Drosophila.","volume":"10","author":"C. G\u00e9minard","year":"2009","journal-title":"Cell Metab"},{"key":"pone.0280529.ref006","doi-asserted-by":"crossref","first-page":"2406","DOI":"10.1073\/pnas.1116050109","article-title":"Conserved role for the Dachshund protein with Drosophila Pax6 homolog Eyeless in Insulin expression","volume":"109","author":"N. Okamoto","year":"2012","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"pone.0280529.ref007","doi-asserted-by":"crossref","first-page":"5729","DOI":"10.1073\/pnas.1319116111","article-title":"Systemic Activin signaling independently regulates sugar homeostasis, cellular metabolism, and pH balance in Drosophila","volume":"111","author":"A. Ghosh","year":"2014","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"pone.0280529.ref008","doi-asserted-by":"crossref","first-page":"123","DOI":"10.1016\/j.cell.2012.08.019","article-title":"Drosophila cytokine Upd2 regulates physiological homeostasis by remotely controlling Insulin secretion","volume":"151","author":"A. Rajan","year":"2012","journal-title":"Cell"},{"key":"pone.0280529.ref009","doi-asserted-by":"crossref","first-page":"83","DOI":"10.1016\/j.devcel.2017.09.007","article-title":"A mechanism coupling system energy sensing to adipokine secretion","volume":"43","author":"A. Rajan","year":"2017","journal-title":"Dev. Cell"},{"key":"pone.0280529.ref010","doi-asserted-by":"crossref","first-page":"786","DOI":"10.1016\/j.cmet.2020.08.017","article-title":"Insulin and Leptin\/Upd2 exert opposing influences on synapse number in fat-sensing neurons","author":"A.E. Brent","year":"2020","journal-title":"Cell Metab"},{"key":"pone.0280529.ref011","doi-asserted-by":"crossref","first-page":"303","DOI":"10.1016\/S0092-8674(03)00072-2","article-title":"TGF-\u03b2 signaling activates steroid hormone receptor expression in neuronal remodeling in the Drosophila brain","volume":"112","author":"X. Zheng","year":"2003","journal-title":"Cell"},{"key":"pone.0280529.ref012","doi-asserted-by":"crossref","first-page":"451","DOI":"10.1016\/S0896-6273(00)80701-1","article-title":"Mosaic analysis with a repressible cell marker for studies of gene function in neuronal morphogenesis","volume":"22","author":"T. Lee","year":"1999","journal-title":"Neuron"},{"issue":"4","key":"pone.0280529.ref013","doi-asserted-by":"crossref","first-page":"jkac019","DOI":"10.1093\/g3journal\/jkac019","article-title":"New resources for the Drosophila 4th chromosome: FRT101F enabled mitotic clones and Bloom syndrome helicase enabled meiotic recombination","volume":"12","author":"S.L. Goldsmith","year":"2022","journal-title":"G3: Genes, Genomes, Genetics"},{"key":"pone.0280529.ref014","doi-asserted-by":"crossref","first-page":"e36548","DOI":"10.1371\/journal.pone.0036548","article-title":"R-Smad competition controls Activin receptor output in Drosophila.","volume":"7","author":"A.J. Peterson","year":"2012","journal-title":"PLoS One"},{"key":"pone.0280529.ref015","doi-asserted-by":"crossref","first-page":"420","DOI":"10.1016\/j.ydbio.2005.09.040","article-title":"Characterization of Upd2, a Drosophila JAK\/STAT pathway ligand","volume":"288","author":"J.C.G. Hombria","year":"2005","journal-title":"Dev. Biol"},{"key":"pone.0280529.ref016","doi-asserted-by":"crossref","first-page":"676","DOI":"10.1038\/nmeth.2019","article-title":"FIJI: an open-source platform for biological-image analysis","volume":"9","author":"J. Schindelin","year":"2012","journal-title":"Nat. Methods"},{"key":"pone.0280529.ref017","doi-asserted-by":"crossref","first-page":"470","DOI":"10.1002\/cne.10467","article-title":"Structure of the vertical and horizontal system neurons of the lobula plate in Drosophila","volume":"454","author":"E.K. Scott","year":"2002","journal-title":"J. Comp. Neurol"},{"key":"pone.0280529.ref018","doi-asserted-by":"crossref","first-page":"791","DOI":"10.1016\/S0092-8674(00)81676-1","article-title":"A pdf neuropeptide gene mutation and ablation of Pdf neurons each cause severe abnormalities of behavioral circadian rhythms in Drosophila","volume":"99","author":"S. Renn","year":"1999","journal-title":"Cell"},{"key":"pone.0280529.ref019","doi-asserted-by":"crossref","first-page":"2596","DOI":"10.1101\/gad.288258.116","article-title":"Circadian and feeding cues drive rhythms of physiology in Drosophila insulin producing cells","volume":"30","author":"A. Barber","year":"2016","journal-title":"Genes Dev"},{"key":"pone.0280529.ref020","doi-asserted-by":"crossref","first-page":"121","DOI":"10.1530\/JOE-22-0006","article-title":"Adiponectin regulates the circadian rhythm of glucose and lipid metabolism","volume":"254","author":"T. Wada","year":"2022","journal-title":"J. Endocrinol"},{"key":"pone.0280529.ref021","doi-asserted-by":"crossref","first-page":"e0187054","DOI":"10.1371\/journal.pone.0187054","article-title":"TGF-\u03b2\/Activin signaling in neurons increases susceptibility to starvation","volume":"12","author":"W. Chng","year":"2017","journal-title":"PLoS One"},{"key":"pone.0280529.ref022","doi-asserted-by":"crossref","first-page":"661","DOI":"10.1016\/S0092-8674(00)81554-8","article-title":"Cycling vrille expression is required for a functional Drosophila clock","volume":"99","author":"J. Blau","year":"1999","journal-title":"Cell"},{"key":"pone.0280529.ref023","doi-asserted-by":"crossref","first-page":"1345","DOI":"10.1093\/genetics\/146.4.1345","article-title":"The vrille gene of Drosophila is a maternal enhancer of dpp and encodes a member of the bZIP family of transcription factors","volume":"146","author":"H. George","year":"1997","journal-title":"Genetics"},{"key":"pone.0280529.ref024","doi-asserted-by":"crossref","first-page":"1299","DOI":"10.1534\/genetics.106.064956","article-title":"dSno facilitates Baboon signaling in the Drosophila brain by switching the affinity of Medea away from Mad and toward dSmad2","volume":"174","author":"N. Takaesu","year":"2006","journal-title":"Genetics"}],"container-title":["PLOS ONE"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0280529","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,23]],"date-time":"2023-01-23T18:30:26Z","timestamp":1674498626000},"score":1,"resource":{"primary":{"URL":"https:\/\/dx.plos.org\/10.1371\/journal.pone.0280529"}},"subtitle":[],"editor":[{"given":"Gregg","family":"Roman","sequence":"first","affiliation":[],"role":[{"role":"editor","vocabulary":"crossref"}]}],"short-title":[],"issued":{"date-parts":[[2023,1,23]]},"references-count":24,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2023,1,23]]}},"URL":"https:\/\/doi.org\/10.1371\/journal.pone.0280529","relation":{},"ISSN":["1932-6203"],"issn-type":[{"value":"1932-6203","type":"electronic"}],"subject":[],"published":{"date-parts":[[2023,1,23]]}}}