{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,10,6]],"date-time":"2026-10-06T14:01:10Z","timestamp":1791295270966,"version":"4.1.0"},"posted":{"date-parts":[[2026,10,2]]},"group-title":"Cell Biology","reference-count":60,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T00:00:00Z","timestamp":1790899200000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/www.biorxiv.org\/about\/FAQ#license"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,10,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Intestinal stem and progenitor cells balance proliferation and lineage commitment to maintain epithelial homeostasis and adapt to environmental challenges. Tuft cells are a rare chemosensory lineage that rapidly expands in response to the cytokine IL-13 during helminth infection, yet how epithelial progenitor states influence this response remains incompletely understood. Using genetic mouse models, intestinal organoids, and single-cell approaches, we identify the Ras guanine nucleotide exchange factor RasGRP1 as an epithelial-intrinsic promoter of efficient tuft cell differentiation.\n                  <jats:italic>Rasgrp1<\/jats:italic>\n                  is expressed in rare crypt epithelial cells distinct from Lgr5-positive stem cells. Once cells entered the tuft cell differentiation trajectory,\n                  <jats:italic>Rasgrp1<\/jats:italic>\n                  deficiency has little impact on tuft cell maturation, including expression of the\n                  <jats:italic>Pou2f3<\/jats:italic>\n                  tuft cell transcription factor. Instead, RasGRP1 acts at the progenitor stage, where it restrains EGFR-driven proliferation and supports a transcriptionally heterogeneous transit-amplifying state, including a subset of cells expressing\n                  <jats:italic>Pou2f3<\/jats:italic>\n                  , that is largely lost upon\n                  <jats:italic>Rasgrp1<\/jats:italic>\n                  deficiency. Consistent with this model, EGFR inhibition restores tuft cell numbers in\n                  <jats:italic>Rasgrp1<\/jats:italic>\n                  -deficient organoids and cooperates with IL-13 to enhance tuft cell differentiation.\n                  <jats:italic>Rasgrp1<\/jats:italic>\n                  -deficient mice exhibit delayed tuft cell hyperplasia and inefficient helminth clearance. Conversely, constitutive epithelial RasGRP1 overexpression, uncoupled from its endogenous regulation, drives spontaneous tuft cell hyperplasia and accelerates parasite clearance, but alters the balance of intestinal epithelial lineages. Together, our findings identify RasGRP1 as a cell-intrinsic regulator that restrains progenitor proliferation and promotes responsiveness to IL-13, thereby coupling growth factor signaling, cell cycle control, and immune-driven epithelial lineage specification.\n                <\/jats:p>","DOI":"10.64898\/2026.09.30.755407","type":"posted-content","created":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T08:25:14Z","timestamp":1790929514000},"source":"Crossref","is-referenced-by-count":0,"title":["RasGRP1 promotes efficient intestinal tuft cell differentiation"],"prefix":"10.64898","author":[{"given":"Lauren A.","family":"Shechtman","sequence":"first","affiliation":[{"name":"Department of Anatomy, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philippe","family":"Depeille","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Smith","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hong-Erh","family":"Liang","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tammie S. Y.","family":"Tam","sequence":"additional","affiliation":[{"name":"CoLabs, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Annabelle","family":"Duflock","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Victor S.","family":"Cortez","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco; CA, U.S.A"},{"name":"Department of Immunology, University of Pittsburg; PA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claire E.","family":"O\u2019Leary","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco; CA, U.S.A"},{"name":"Department of Pediatrics, University of Wisconsin-Madison; WI, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan","family":"Shen","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California, San Francisco; CA, U.S.A"},{"name":"CoLabs, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wouter","family":"Bos","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabriela","family":"Fradiadakis","sequence":"additional","affiliation":[{"name":"CoLabs, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexis","family":"Combes","sequence":"additional","affiliation":[{"name":"CoLabs, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hugo","family":"Gonzalez","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California, San Francisco; CA, U.S.A"},{"name":"Centro Basal Ciencia & Vida, Fundaci\u00f3n Ciencia & Vida; Santiago, Chile"},{"name":"Facultad de Ciencias para el Cuidado de la Salud, Universidad San Sebastian; Santiago, Chile"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard M.","family":"Locksley","sequence":"additional","affiliation":[{"name":"Department of Medicine, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4746-2811","authenticated-orcid":false,"given":"Jeroen P.","family":"Roose","sequence":"additional","affiliation":[{"name":"Department of Anatomy, University of California, San Francisco; CA, U.S.A"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026100606450453000_2026.09.30.755407v1.1","doi-asserted-by":"publisher","DOI":"10.1038\/nature06196"},{"key":"2026100606450453000_2026.09.30.755407v1.2","doi-asserted-by":"publisher","DOI":"10.1038\/s41580-020-0278-0"},{"key":"2026100606450453000_2026.09.30.755407v1.3","doi-asserted-by":"publisher","DOI":"10.1016\/j.stem.2020.09.011"},{"key":"2026100606450453000_2026.09.30.755407v1.4","doi-asserted-by":"crossref","unstructured":"C. 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