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While high expression of integrins has been correlated with stemness, there is limited direct evidence that integrins mediate keratinocyte retention within the basal layer. Here, we generate mosaic, epidermal-specific loss of integrin-\u03b24 (encoded by Itgb4) or its ligand, laminin-\u03b13\u03b23\u03b32 (Lama3), in mouse using an in utero lentiviral-mediated approach. Although mutations in these genes cause postnatal skin blistering in mice and humans, we observe no evidence of dermal-epidermal separation embryonically. Despite no obvious alterations to apicobasal polarity, Itgb4-deficient basal cells show mild defects in oriented cell divisions, with increased oblique divisions and altered telophase correction. However, differentiation via delamination, whereby basal keratinocytes lose adhesion to the underlying basement membrane and transit into the suprabasal layer, is elevated upon Itgb4 or Lama3 loss. Notably, hyperactive Notch signaling both decreases integrin-\u03b24 expression and increases delamination, while deletion of the Notch effector Rbpj has the opposite effect. These findings conclusively demonstrate a causal role for hemidesmosomes in regulating epidermal differentiation through both mitotic and non-mitotic mechanisms, and shed additional light on the programs regulating delamination.<\/jats:p>","DOI":"10.1242\/dev.205210","type":"journal-article","created":{"date-parts":[[2026,4,2]],"date-time":"2026-04-02T08:46:06Z","timestamp":1775119566000},"source":"Crossref","is-referenced-by-count":6,"title":["Hemidesmosomes and Notch signaling regulate epidermal differentiation via delamination"],"prefix":"10.1242","volume":"153","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-3865-6956","authenticated-orcid":false,"given":"Juliet S.","family":"King","sequence":"first","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, The University of North Carolina 1 Departments of Pathology & Laboratory Medicine and Biology , , Chapel Hill, NC 27959 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kendall J.","family":"Lough","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, The University of North Carolina 1 Departments of Pathology & Laboratory Medicine and Biology , , Chapel Hill, NC 27959 ,","place":["USA"]},{"name":"Center for Gastrointestinal Biology and Disease, Bowles Center for Alcohol Studies, The University of North Carolina 2 , Chapel Hill, NC 27959 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9975-7334","authenticated-orcid":false,"given":"Scott E.","family":"Williams","sequence":"additional","affiliation":[{"name":"Lineberger Comprehensive Cancer Center, The University of North Carolina 1 Departments of Pathology & Laboratory Medicine and Biology , , Chapel Hill, NC 27959 ,","place":["USA"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,4,16]]},"reference":[{"key":"2026041608244760200_DEV205210C1","doi-asserted-by":"publisher","first-page":"425","DOI":"10.1016\/0092-8674(90)90175-E","article-title":"Changes in keratinocyte adhesion during terminal differentiation: Reduction in fibronectin binding precedes \u03b15\u03b21 integrin loss from the cell surface","volume":"63","author":"Adams","year":"1990","journal-title":"Cell"},{"key":"2026041608244760200_DEV205210C2","doi-asserted-by":"publisher","first-page":"821","DOI":"10.1038\/nm.2167","article-title":"Rapid functional dissection of genetic networks via tissue-specific transduction and RNAi in mouse embryos","volume":"16","author":"Beronja","year":"2010","journal-title":"Nat. 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