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Extracellular matrix protein SLIT3, a classical axon guidance molecule, has been identified as a clastokine linking bone resorption to formation. However, its role in odontogenesis is not well-documented. Thus, our study aimed to explore the effects and mechanisms of SLIT3 on SCAP proliferation and differentiation. Analysis of developing mouse molars showed that while\n                    <jats:italic>Slit3<\/jats:italic>\n                    mRNA was restricted to the dental mesenchyme, the SLIT3 protein was prominently detected on both odontoblasts and adjacent epithelial ameloblasts. Real time polymerase chain reaction (RT-PCR) and Western blot assays confirmed increased SLIT3 expression during SCAP odontogenic differentiation. SLIT3 siRNA knockdown and recombinant human SLIT3 (rhSLIT3) protein treatments were administered to SCAP. Cell Counting Kit-8 (CCK8) assays indicated that SLIT3 promotes SCAP proliferation, while alkaline phosphatase (ALP) and Alizarin red staining showed increased mineralization. Odontogenic markers DMP-1 and DSPP were also modulated accordingly. Additionally, rhSLIT3 treatment enhanced p-Akt and p-GSK3\u03b2 levels in SCAP, promoting \u03b2-catenin nuclear translocation. The effects of SLIT3 were negated with an Akt\/GSK3\u03b2\/\u03b2-catenin signaling pathway inhibitor. Collectively, our data suggest that SLIT3 promotes SCAP proliferation and odontogenic differentiation via the Akt\/GSK3\u03b2\/\u03b2-catenin signaling pathway activation.\n                  <\/jats:p>","DOI":"10.1038\/s41368-026-00426-7","type":"journal-article","created":{"date-parts":[[2026,4,12]],"date-time":"2026-04-12T23:03:10Z","timestamp":1776034990000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["SLIT3: a novel regulator of odontogenic differentiation through Akt\/GSK3\u03b2\/\u03b2-catenin signaling pathway"],"prefix":"10.1038","volume":"18","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0003-9226","authenticated-orcid":false,"given":"Lingyu","family":"Jiang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8681-3413","authenticated-orcid":false,"given":"Liu","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fan","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yujia","family":"Cui","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8156-0322","authenticated-orcid":false,"given":"Jing","family":"Xie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dongzhe","family":"Song","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7511-9872","authenticated-orcid":false,"given":"Yi","family":"Fan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0779-5729","authenticated-orcid":false,"given":"Dingming","family":"Huang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3356-2635","authenticated-orcid":false,"given":"Jianxun","family":"Sun","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2026,4,13]]},"reference":[{"key":"426_CR1","doi-asserted-by":"publisher","first-page":"648","DOI":"10.1016\/j.joen.2020.02.004","volume":"46","author":"J Bi","year":"2020","unstructured":"Bi, J., Liu, Y., Liu, X. 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