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Despite these cells\u2019 critical roles in intestinal homeostasis and disease, few studies have described genes that are essential to transit-amplifying cell function. We report that RNA methyltransferase-like 3 (METTL3) is required for survival of transit-amplifying cells in the murine small intestine. Transit-amplifying cell death after METTL3 deletion was associated with crypt and villus atrophy, loss of absorptive enterocytes, and uniform wasting and death in METTL3-depleted mice. Sequencing of polysome-bound and methylated RNAs in enteroids and in vivo demonstrated decreased translation of hundreds of methylated transcripts after METTL3 deletion, particularly transcripts involved in growth factor signal transduction such as\n                    <jats:italic>Kras<\/jats:italic>\n                    . Further investigation verified a relationship between METTL3 and\n                    <jats:italic>Kras<\/jats:italic>\n                    methylation and protein levels in vivo. Our study identifies METTL3 as an essential factor supporting the homeostasis of small intestinal tissue via direct maintenance of transit-amplifying cell survival. We highlight the crucial role of RNA modifications in regulating growth factor signaling in the intestine with important implications for both homeostatic tissue renewal and epithelial regeneration.\n                  <\/jats:p>","DOI":"10.1172\/jci.insight.171657","type":"journal-article","created":{"date-parts":[[2023,10,26]],"date-time":"2023-10-26T12:01:41Z","timestamp":1698321701000},"source":"Crossref","is-referenced-by-count":15,"title":["Intestinal transit-amplifying cells require METTL3 for growth factor signaling and cell survival"],"prefix":"10.1172","volume":"8","author":[{"given":"Charles H.","family":"Danan","sequence":"first","affiliation":[{"name":"Division of Gastroenterology, Hepatology, and Nutrition, Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Perelman School of Medicine;"},{"name":"Medical Scientist Training Program, Perelman School of Medicine; and"},{"name":"Perelman School of Medicine, University of Pennsylvania, Philadelphia, 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