{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,23]],"date-time":"2026-08-23T17:15:50Z","timestamp":1787505350745,"version":"build-2736575974"},"reference-count":43,"publisher":"The Company of Biologists","issue":"3","license":[{"start":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T00:00:00Z","timestamp":1775692800000},"content-version":"vor","delay-in-days":25,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0"}],"funder":[{"name":"Merck Sharp and Dohme (MSD) Avenir Fund"},{"DOI":"10.13039\/501100001665","name":"Agence Nationale de la Recherche","doi-asserted-by":"crossref","award":["ANR-21-PMRB-0004"],"award-info":[{"award-number":["ANR-21-PMRB-0004"]}],"id":[{"id":"10.13039\/501100001665","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100017337","name":"Institut des maladies g\u00e9n\u00e9tiques Imagine","doi-asserted-by":"crossref","id":[{"id":"10.13039\/100017337","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,15]]},"abstract":"<jats:title>ABSTRACT<\/jats:title>\n                  <jats:p>Meckel's and condylar cartilages are key to mandible development, with Meckel's cartilage acting as a template and condylar cartilage as a growth center. In achondroplasia, the most common form of genetic dwarfism, abnormalities of these cartilages lead to micrognathia, with significant functional repercussions for affected individuals. How FGFR3 overactivation in achondroplasia disrupts Meckel's and condylar cartilages is largely unknown. Our aim was to identify the pathways driving these disruptions by analyzing the genes expressed in these cartilages in a mouse model mimicking achondroplasia. Using cartilage laser-microdissection and RNA-sequencing analyses, we first compared the transcriptome of Meckel's and condylar cartilages from E16.5 embryos of control and Fgfr3Y367C\/+ mice. Over 900 genes were differentially expressed, including the Dkk1 gene, which encodes an inhibitor of \u03b2-catenin-dependent Wnt signaling and was significantly overexpressed in chondrocytes of Fgfr3 mutants in both Meckel's and condylar cartilages. Immunostaining of sections of the cartilages confirmed the high expression at the protein level. Primary cultures of Meckel's cartilage chondrocytes showed that, in Fgfr3Y367C\/+ mutants, activation of the canonical Wnt pathway with Wnt3a was reduced, while a Dkk1 antagonist increased Wnt activity, suggesting that Dkk1 overexpression was responsible for decreased canonical Wnt activity in mutants. In a mandible organ culture model, inhibition of Dkk1 also significantly increased the mandible size, due to an increased elongation of the condylar cartilage of mutants, as seen after tissue clearing and Sox9 immunolabeling. In this cartilage, increased proliferation and defective differentiation into hypertrophic chondrocytes was partially corrected by Dkk1 inhibition. Our data suggest that dysregulation of Wnt\/\u03b2-catenin activity due to Fgfr3 gain-of function mutation constitutes an important underlying mechanism in craniofacial defects observed in achondroplasia.<\/jats:p>","DOI":"10.1242\/bio.062540","type":"journal-article","created":{"date-parts":[[2026,4,9]],"date-time":"2026-04-09T13:18:48Z","timestamp":1775740728000},"source":"Crossref","is-referenced-by-count":1,"title":["Dkk1 inhibition restores mandibular growth in an achondroplasia mouse model"],"prefix":"10.1242","volume":"15","author":[{"given":"Briantana","family":"Raveendranathan","sequence":"first","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentin","family":"Estibals","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eric","family":"Pulido","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Clara","family":"Lemoine","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nabil","family":"Kaci","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachel","family":"Pereur","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mohammed","family":"Zarhrate","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 2 Genomics Platform , , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"S\u00e9bastien","family":"Dupichaud","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 3 Imaging Platform , , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emilie","family":"Dambroise","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Legeai-Mallet","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9417-3970","authenticated-orcid":false,"given":"Martin","family":"Biosse Duplan","sequence":"additional","affiliation":[{"name":"Institut Imagine, UMR INSERM 1163, Universit\u00e9 Paris Cit\u00e9 1 , 75015 Paris ,","place":["France"]},{"name":"UFR Odontologie, Universit\u00e9 Paris Cit\u00e9 and Hopital Bretonneau, APHP 4 , 75018 Paris ,","place":["France"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"237","published-online":{"date-parts":[[2026,4,9]]},"reference":[{"key":"2026040909284318500_BIO062540C1","doi-asserted-by":"publisher","first-page":"e1004479","DOI":"10.1371\/journal.pgen.1004479","article-title":"Wnt signaling interacts with Bmp and Edn1 to regulate dorsal-ventral patterning and growth of the craniofacial skeleton","volume":"10","author":"Alexander","year":"2014","journal-title":"PLoS Genet."},{"key":"2026040909284318500_BIO062540C2","doi-asserted-by":"publisher","first-page":"2997","DOI":"10.1093\/hmg\/ddw153","article-title":"Meckel's and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible","volume":"25","author":"Biosse Duplan","year":"2016","journal-title":"Hum. 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