{"title":"Cranial base synostosis in mice caused by upregulation of Wnt following partial inhibition of Shh.","authors":"Jiangping Chen, Chengyan Ren, Chuanqing Mao, Yongzhen Lai, Meng Lu, Yuanjing Jiang, Weihui Chen","doi":"10.1186/s12915-025-02381-x","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>The cranial base develops from multipotent mesenchymal cells through endochondral ossification. Genetic ablation of Sonic hedgehog (Shh) or Smoothened (Smo) leads to early apoptosis of cranial base cells, thus limiting the study of their role in the early development of cranial base. Our previous studies have shown that administration of 150 mg/kg Vismodegib (a Smo-specific small molecule antagonist) in E9.5- or E10.5-mice leads to premature mineralization of the skull base synchondroses. In the current study, we further investigated the molecular mechanisms underlying this model.</p><p><strong>Results: </strong>Mice exposed to Vismodegib exhibit premature hypertrophic differentiation and osteogenesis of the cranial base synchondroses after E14.5. However, the expression of Patched1 (Ptch1), Gli1, parathyroid hormone-related protein (PTHrP), and Phh3 was not downregulated in exposure mice. We demonstrate that Shh and Wnt signaling pathways were activated in the cranial base region at E10.5. Administration of Vismodegib at E10.5 transiently inhibited Shh signaling in the cranial base area and caused upregulation of β-catenin expression along with ectopic expression of lymphoid enhancer-binding factor 1 (Lef1) and Runx2 in the ventral mesenchymal cells of the cranial base primordium at E12.5. Diverse degrees of cranial base craniosynostosis induced by various doses of Vismodegib suggest a dose-dependent effect of Shh in early basicranium development.</p><p><strong>Conclusions: </strong>The present experiment suggests that early activation of Shh standardizes normal embryonic development of cranial base after initial morphogenesis, which may be mediated through the \"antagonistic\" effect of Shh signaling on Wnt signaling. Our study provides new insights into the role of signal-crosstalk in early morphogenesis of the cranial base.</p>","PeriodicalId":9339,"journal":{"name":"BMC Biology","volume":"23 1","pages":"268"},"PeriodicalIF":4.5000,"publicationDate":"2025-08-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12382131/pdf/","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"BMC Biology","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.1186/s12915-025-02381-x","RegionNum":1,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOLOGY","Score":null,"Total":0}
引用次数: 0
Abstract
Background: The cranial base develops from multipotent mesenchymal cells through endochondral ossification. Genetic ablation of Sonic hedgehog (Shh) or Smoothened (Smo) leads to early apoptosis of cranial base cells, thus limiting the study of their role in the early development of cranial base. Our previous studies have shown that administration of 150 mg/kg Vismodegib (a Smo-specific small molecule antagonist) in E9.5- or E10.5-mice leads to premature mineralization of the skull base synchondroses. In the current study, we further investigated the molecular mechanisms underlying this model.
Results: Mice exposed to Vismodegib exhibit premature hypertrophic differentiation and osteogenesis of the cranial base synchondroses after E14.5. However, the expression of Patched1 (Ptch1), Gli1, parathyroid hormone-related protein (PTHrP), and Phh3 was not downregulated in exposure mice. We demonstrate that Shh and Wnt signaling pathways were activated in the cranial base region at E10.5. Administration of Vismodegib at E10.5 transiently inhibited Shh signaling in the cranial base area and caused upregulation of β-catenin expression along with ectopic expression of lymphoid enhancer-binding factor 1 (Lef1) and Runx2 in the ventral mesenchymal cells of the cranial base primordium at E12.5. Diverse degrees of cranial base craniosynostosis induced by various doses of Vismodegib suggest a dose-dependent effect of Shh in early basicranium development.
Conclusions: The present experiment suggests that early activation of Shh standardizes normal embryonic development of cranial base after initial morphogenesis, which may be mediated through the "antagonistic" effect of Shh signaling on Wnt signaling. Our study provides new insights into the role of signal-crosstalk in early morphogenesis of the cranial base.
期刊介绍:
BMC Biology is a broad scope journal covering all areas of biology. Our content includes research articles, new methods and tools. BMC Biology also publishes reviews, Q&A, and commentaries.