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In addition to respiratory, digestive, and reproductive pathologies, patients with CF also exhibit higher rates of enamel defects. CFTR is an anion channel expressed in maturation-stage ameloblasts and is known for its role in chloride and bicarbonate conductance, a function thought to promote enamel mineralization through the neutralization of protons released during hydroxyapatite formation. Previous studies of CFTR global knockout mice have shown hypomineralization and acidification of the maturation-stage enamel matrix. However, the systemic nature of CF and the contribution of extrinsic factors may contribute to these findings. To determine how CFTR specifically contributes to amelogenesis, we generated a conditional knockout mouse in which CFTR loss-of-function is driven by Cre expression under the promoter of the maturation-stage ameloblast marker,\n                    <jats:italic>Odam.<\/jats:italic>\n                    CFTR loss-of-function resulted in the formation of hypomineralized enamel. The enamel matrix was acidified, and loss of matrix pH cycling coincided with arrested ameloblast modulation as indicated by failed re-localization of tight\/ gap junctions and ion transporters to the ameloblast distal membrane. Amelogenin hydrolysis was reduced and retained in the maturing enamel matrix, which was associated with reduced\n                    <jats:italic>Klk4<\/jats:italic>\n                    expression and activity. Transcriptional analyses of incisor ameloblasts showed reduced expression of acid-base regulators, consistent with dysregulation of both intracellular and extracellular pH. Together, these findings show multiple functions of CFTR in incisor enamel maturation, including regulation of intra\/ extracellular pH, ameloblast modulation, and extracellular matrix remodeling.\n                  <\/jats:p>","DOI":"10.1007\/s00223-026-01539-1","type":"journal-article","created":{"date-parts":[[2026,5,4]],"date-time":"2026-05-04T11:47:56Z","timestamp":1777895276000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["The Role of the Cystic Fibrosis Transmembrane Conductance Regulator (CFTR) in Enamel Formation"],"prefix":"10.1007","volume":"117","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-3548-4148","authenticated-orcid":false,"given":"Jake","family":"Ngu","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Charles M.","family":"Met","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Atoosa","family":"Heidari Bigvand","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2373-1696","authenticated-orcid":false,"given":"Yan","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2107-6229","authenticated-orcid":false,"given":"Pamela K.","family":"Den Besten","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,5,4]]},"reference":[{"key":"1539_CR1","doi-asserted-by":"publisher","first-page":"S23","DOI":"10.1152\/physrev.1999.79.1.S23","volume":"79","author":"DN Sheppard","year":"1999","unstructured":"Sheppard DN, Welsh MJ (1999) Structure and Function of the CFTR Chloride Channel. 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