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Depending on the specific ligand and co-receptor interacting with it, CD271 mediates various cellular responses in keratinocytes. In vitro analysis shows that it is implicated in the transition from human interfollicular keratinocyte stem cells to transient amplifying cells. However, no in vivo models are available to dissect the complexity of these mechanisms, including the effect on the inflammatory response. Here, we develop and characterize two novel mouse models, the CD271cKO and the CD271ciKO, where CD271 is conditionally absent in keratinocytes during development or after topical induction, respectively. By histology, functional assay, transcriptomics and molecular analysis, we identified substantial skin changes correlated to CD271 deletion, including epidermal hyperproliferation, \u201cactivated\u201d keratinocyte signature, and a delayed in the differentiation process, mostly linked to PI3K\/Akt and mitogenic pathways-dependent processes. KO keratinocyte displays upregulation of Ki67, PCNA, KRT5, KRT6, and ERK phosphorylation, as well as major expression of IL1\u03b1, Cxcl15, and TGF\u03b2. KO skin resemble dysplastic skin conditions, including the recruitment of immune cells, particularly T cells, macrophages, and neutrophils, and release of inflammatory cytokines involved in TNF, JAK\/Stat, IL17, and PI3k\/Akt signaling pathways. Overall, our data defines CD271 as a crucial regulator of skin homeostasis. Therefore, our models represent an exceptionally useful tool for the characterization of skin pathophysiology linked to CD271 and possibly for developing appropriate therapies.<\/jats:p>","DOI":"10.1038\/s41419-025-08062-5","type":"journal-article","created":{"date-parts":[[2025,10,21]],"date-time":"2025-10-21T13:00:58Z","timestamp":1761051658000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["CD271 orchestrates skin structure, differentiation, and inflammation via PI3K\/Akt and PKC\u03b1\/ERK pathways"],"prefix":"10.1038","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-7619-660X","authenticated-orcid":false,"given":"Marika","family":"Quadri","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Luca","family":"Reggiani Bonetti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Pellegrini","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2232-7090","authenticated-orcid":false,"given":"Mirco","family":"Mastrangelo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Andrea","family":"Caporali","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Cristina","family":"Vaschieri","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2126-4147","authenticated-orcid":false,"given":"Roberta","family":"Lotti","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria Concetta","family":"Fargnoli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Carlo","family":"Pincelli","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5667-5766","authenticated-orcid":false,"given":"Alessandra","family":"Marconi","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0812-5524","authenticated-orcid":false,"given":"Elisabetta","family":"Palazzo","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2025,10,21]]},"reference":[{"key":"8062_CR1","doi-asserted-by":"publisher","first-page":"F1000","DOI":"10.12688\/f1000research.19174.1","volume":"8","author":"M Bothwell","year":"2019","unstructured":"Bothwell M. 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