{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T01:56:41Z","timestamp":1792202201697,"version":"4.4.0"},"reference-count":57,"publisher":"The Company of Biologists","issue":"14","license":[{"start":{"date-parts":[[2025,7,15]],"date-time":"2025-07-15T00:00:00Z","timestamp":1752537600000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/www.biologists.com\/user-licence-1-2\/"}],"funder":[{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","award":["NNF17CC0027852"],"award-info":[{"award-number":["NNF17CC0027852"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/501100009708","name":"Novo Nordisk Foundation","doi-asserted-by":"crossref","award":["NNF21CC0073729"],"award-info":[{"award-number":["NNF21CC0073729"]}],"id":[{"id":"10.13039\/501100009708","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,7,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n               <jats:p>In the developing mouse pancreas, Notch signaling first maintains multipotent pancreatic progenitor cells (MPCs), suppressing early endocrine differentiation, then promotes their adoption of a duct\/endocrine-bipotent progenitor (BP) fate at the expense of Notch-independent pro-acinar progenitors (PACs). Active Notch signaling is terminated by Notch intracellular domain (NICD) degradation via the E3 ubiquitin ligase SCFFbxw7, which also regulates the stability of other unidentified substrates in developing pancreas. We show here that endodermal deletion of the substrate recognition component Fbxw7 dose-dependently suppresses early endocrine differentiation, which is consistent with Notch1 ICD (N1ICD) upregulation in MPCs, then perturbs later acinar and ductal morphogenesis. PACs of Fbxw7 mouse mutants ectopically express Sox9 and N1ICD, which is associated with defective acinar differentiation, while their ducts are cystic with intermingled endocrine cells and inappropriate external openings. While genetic blockade of Notch transduction normalizes early endocrine differentiation in Fbxw7 mouse mutants, it is unable to rescue the later acinar phenotype, which, instead, can be normalized by Sox9 haploinsufficiency. Fbxw7 is thus required to limit N1ICD and Sox9 perdurance in the developing pancreas to enable appropriate early endocrine differentiation and to allow the complete segregation of BP and PAC lineages.<\/jats:p>","DOI":"10.1242\/dev.204596","type":"journal-article","created":{"date-parts":[[2025,7,2]],"date-time":"2025-07-02T10:00:10Z","timestamp":1751450410000},"source":"Crossref","is-referenced-by-count":1,"title":["Fbxw7 regulates N1ICD and Sox9 perdurance during pancreas development to ensure proper cell lineage allocation and segregation"],"prefix":"10.1242","volume":"152","author":[{"given":"Diana Wichmann","family":"Graff","sequence":"first","affiliation":[{"name":"Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) 1 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"University of Copenhagen 1 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-0367-4219","authenticated-orcid":false,"given":"Emilie Liv","family":"Bang-Jensen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW 2 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"University of Copenhagen 2 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7231-1487","authenticated-orcid":false,"given":"Anuska la Rosa","family":"Egeskov-Madsen","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) 1 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"University of Copenhagen 1 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0858-590X","authenticated-orcid":false,"given":"Palle","family":"Serup","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) 1 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"University of Copenhagen 1 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW 2 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"University of Copenhagen 2 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5782-6020","authenticated-orcid":false,"given":"Philip A.","family":"Seymour","sequence":"additional","affiliation":[{"name":"Novo Nordisk Foundation Center for Stem Cell Biology (DanStem) 1 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"University of Copenhagen 1 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"Novo Nordisk Foundation Center for Stem Cell Medicine, reNEW 2 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]},{"name":"University of Copenhagen 2 , Faculty of Health and Medical Sciences , , DK-2200 Copenhagen ,","place":["Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2025,7,28]]},"reference":[{"key":"2025072806170631900_DEV204596C1","doi-asserted-by":"publisher","first-page":"1744","DOI":"10.1242\/dev.075804","article-title":"Notch-mediated patterning and cell fate allocation of pancreatic progenitor cells","volume":"139","author":"Afelik","year":"2012","journal-title":"Development"},{"key":"2025072806170631900_DEV204596C2","doi-asserted-by":"publisher","first-page":"925","DOI":"10.1369\/jhc.7A7226.2007","article-title":"An improved method for three-dimensional reconstruction of protein expression patterns in intact mouse and chicken embryos and organs","volume":"55","author":"Ahnfelt-R\u00f8nne","year":"2007","journal-title":"J. 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