Journal Article

Cranial base synostosis in mice caused by upregulation of Wnt following partial inhibition of Shh

Lu, Meng, Ren, Chengyan, Chen, Jiangping, Jiang, Yuanjing, Lai, Yongzhen, Chen, Weihui, Mao, Chuanqing

2025

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Ablation / Ablation (Surgery) / Analysis / Anilides / Animals / Apoptosis / Basicranium / Biomedical and Life Sciences / Birth defects / Cartilage / Cbfa-1 protein / Chondrocytes - physiology / Cranial base / Craniofacial dysostosis / Craniosynostoses - etiology / Craniosynostoses - metabolism / Craniosynostoses - pathology / Craniosynostosis / Diagnosis / Dosage and administration / Dysostosis / Ectopic expression / Embryogenesis / Embryonic growth stage / Embryos / Endochondral bone / Genetic aspects / Genotype & phenotype / Hedgehog protein / Hedgehog proteins / Hedgehog Proteins - antagonists & inhibitors / Hedgehog Proteins - metabolism / Life Sciences / Mesenchyme / Mice / Mineralization / Molecular modelling / Morphogenesis / Ossification / Osteogenesis / Parathyroid hormone / Parathyroid hormone-related protein / Patient outcomes / Pyridines / Research Article / Risk factors / Skull / Skull Base - embryology / Skull Base - metabolism / Skull Base - pathology / Sonic hedgehog / Synchondrosis / Up-Regulation / Vismodegib / Wnt / Wnt protein / Wnt Signaling Pathway / β-Catenin