Defining the critical period of hedgehog pathway inhibitor‐induced cranial base dysplasia in mice

• Published in: Developmental dynamics Vol. 250; no. 4; pp. 527 - 541
• Main Authors: Chen, Jiangping, Tang, Wenbing, Lin, Chengquan, Hong, Yuhang, Mao, Chuanqing, Lai, Yongzhen, Liao, Caiyu, Lin, Minkui, Chen, Weihui
• Format: Journal Article
• Language: English
• Published: Hoboken, USA John Wiley & Sons, Inc 01-04-2021; Wiley Subscription Services, Inc
• Subjects: Anilides; Animals; Axial skeleton; Biomedical materials; Chondrocytes; Chondrogenesis; cranial base craniosynostosis; cranial base fenestra; Cranial sutures; Craniofacial Abnormalities - etiology; Craniofacial Abnormalities - metabolism; Craniosynostosis; Critical period; Dysostosis; Dysplasia; Embryos; Female; Head; Hedgehog protein; Hedgehog Proteins - antagonists & inhibitors; Hedgehog Proteins - metabolism; hedgehog signaling; Hypoplasia; Inhibitors; Male; Mice; Mice, Inbred ICR; Osteogenesis; Pattern formation; Prenatal development; Pyridines; Rodents; Signal transduction; Skull; Skull Base - abnormalities; Temporal resolution; vismodegib; cranial base fenestra; vismodegib; cranial base craniosynostosis; hedgehog signaling
• ISSN: 1058-8388; 1097-0177
• DOI: 10.1002/dvdy.270

Background
The hedgehog signaling pathway is critical for developmental patterning of the limb, craniofacial and axial skeleton. Disruption of this pathway in mice leads to a series of structural malformations, but the exact role and critical period of the Hh pathway in the early development of the cranial base have been rarely described.
Results
Embryos exposed to vismodegib from E7.5, E9.5, and E10.5 had a higher percentage of cranial base fenestra. The peak incidence of hypoplasia in sphenoid winglets and severe craniosynostosis in cranial base synchondroses was observed when vismodegib was administered between E9.5 and E10.5. Cranial base craniosynostosis results from accelerating terminal differentiation of chondrocytes and premature osteogenesis.
Conclusions
We define the critical periods for the induction of cranial base deformity by vismodegib administration at a meticulous temporal resolution. Our findings suggest that the Hh pathway may play a vital role in the early development of the cranial base. This research also establishes a novel and easy‐to‐establish mouse model of synostosis in the cranial base using a commercially available pathway‐selective inhibitor.
Key Findings
Embryos exposed to vismodegib to E7.5,E9.5 and E10.5 caused diverged cranial base phenotype.
Treatment of vismodegib at E9.5 and E10.5 can lead to hypoplasia in sphenoid winglets, cranial base fenestra and severe craniosynostosis in cranial base.
The cranial base craniosynostosis result from premature differentiation and osteogenesis of synchondrosis.