{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"bioRxiv"}],"indexed":{"date-parts":[[2026,1,15]],"date-time":"2026-01-15T21:15:10Z","timestamp":1768511710045,"version":"3.49.0"},"posted":{"date-parts":[[2024,5,24]]},"group-title":"Developmental Biology","reference-count":44,"publisher":"openRxiv","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2024,5,24]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:p>\n                  Malocclusions are common craniofacial malformations which cause quality of life and health problems if left untreated. Unfortunately, the current treatment for severe skeletal malocclusion is invasive surgery. Developing improved therapeutic options requires a deeper understanding of the cellular mechanisms responsible for determining jaw bone length. We have recently shown that neural crest mesenchyme (NCM) can alter jaw length by controlling recruitment and function of mesoderm-derived osteoclasts. Transforming growth factor beta (TGF-\u03b2) signaling is critical to craniofacial development by directing bone resorption and formation, and heterozygous mutations in TGF-\u03b2 type I receptor (\n                  <jats:italic>TGFBR1)<\/jats:italic>\n                  are associated with micrognathia in humans. To identify what role TGF-\u03b2 signaling in NCM plays in controlling osteoclasts during mandibular development, mandibles of mouse embryos deficient in the gene encoding\n                  <jats:italic>Tgfbr1<\/jats:italic>\n                  specifically in NCM were analyzed. Our lab and others have demonstrated that\n                  <jats:italic>Tgfbr1<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>fl\/fl<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>;Wnt1-Cre<\/jats:italic>\n                  mice display significantly shorter mandibles with no condylar, coronoid, or angular processes. We hypothesize that TGF-\u03b2 signaling in NCM can also direct later bone remodeling and further regulate late embryonic jaw bone length. Interestingly, analysis of mandibular bone through micro-computed tomography and Masson\u2019s trichrome revealed no significant difference in bone quality between the\n                  <jats:italic>Tgfbr1<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>fl\/fl<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>;Wnt1-Cre<\/jats:italic>\n                  mice and controls, as measured by bone perimeter\/bone area, trabecular rod-like diameter, number and separation, and gene expression of Collagen type 1 alpha 1 (\n                  <jats:italic>Col1\u03b11<\/jats:italic>\n                  ) and Matrix metalloproteinase 13 (\n                  <jats:italic>Mmp13<\/jats:italic>\n                  ). Though there was not a difference in localization of bone resorption within the mandible indicated by TRAP staining,\n                  <jats:italic>Tgfbr1<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>fl\/fl<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>;Wnt1-Cre<\/jats:italic>\n                  mice had approximately three-fold less osteoclast number and perimeter than controls. Gene expression of receptor activator of nuclear factor kappa-\u03b2 (\n                  <jats:italic>Rank<\/jats:italic>\n                  ) and\n                  <jats:italic>Mmp9<\/jats:italic>\n                  , markers of osteoclasts and their activity, also showed a three-fold decrease in\n                  <jats:italic>Tgfbr1<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>fl\/fl<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>;Wnt1-Cre<\/jats:italic>\n                  mandibles. Evaluation of osteoblast-to-osteoclast signaling revealed no significant difference between\n                  <jats:italic>Tgfbr1<\/jats:italic>\n                  <jats:sup>\n                    <jats:italic>fl\/fl<\/jats:italic>\n                  <\/jats:sup>\n                  <jats:italic>;Wnt1-Cre<\/jats:italic>\n                  mandibles and controls, leaving the specific mechanism unresolved. Finally, pharmacological inhibition of\n                  <jats:italic>Tgfbr1<\/jats:italic>\n                  signaling during the initiation of bone mineralization and resorption significantly shortened jaw length in embryos. We conclude that TGF-\u03b2 signaling in NCM decreases mesoderm-derived osteoclast number, that TGF-\u03b2 signaling in NCM impacts jaw length late in development, and that this osteoblast-to-osteoclast communication may be occurring through an undescribed mechanism.\n                <\/jats:p>","DOI":"10.1101\/2024.05.24.595783","type":"posted-content","created":{"date-parts":[[2024,5,25]],"date-time":"2024-05-25T03:20:12Z","timestamp":1716607212000},"source":"Crossref","is-referenced-by-count":1,"title":["TGF-\u03b2 Signaling in Cranial Neural Crest Affects Late-Stage Mandibular Bone Resorption and Length"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2003-4625","authenticated-orcid":false,"given":"Claire J.","family":"Houchen","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Saif","family":"Ghanem","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9432-510X","authenticated-orcid":false,"given":"Vesa","family":"Kaartinen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8698-7808","authenticated-orcid":false,"given":"Erin Ealba","family":"Bumann","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"54368","reference":[{"issue":"3","key":"2024052804351440000_2024.05.24.595783v1.1","doi-asserted-by":"crossref","first-page":"340","DOI":"10.1055\/s-0039-1698971","article-title":"The genetic basis of facial skeletal characteristics and its relation with orthodontics","volume":"6","year":"2012","journal-title":"Eur J Dent"},{"key":"2024052804351440000_2024.05.24.595783v1.2","doi-asserted-by":"crossref","first-page":"74","DOI":"10.1111\/j.1749-6632.1998.tb08928.x","article-title":"Surgical treatment for fetal disease","volume":"847","year":"1998","journal-title":"The state of the art. 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