Defining a critical period in calvarial development for Hedgehog pathway antagonist-induced frontal bone dysplasia in mice  

作　　者：Yuanjing Jiang Shixian Zhang Chuanqing Mao Yongzhen Lai Di Wu Hu Zhao Caiyu Liao Weihui Chen 

机构地区：[1]Department of Oral and Maxillofacial Surgery, Union Hospital, Fujian Medical University [2]Institute of Stomatology, Fujian Medical University [3]School and Hospital of Stomatology, Fujian Medical University [4]Department of Restorative Sciences, School of Dentistry, Texas A&M University [5]Fujian Biological Materials Engineering and Technology Center of Stomatology

出　　处：《International Journal of Oral Science》2019年第1期58-69,共12页国际口腔科学杂志（英文版）

基　　金：supported by the National Natural Science Foundation of China (31070838)

摘　　要：The Hedgehog(Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development.Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 or 150 mg·kg^(-1) body weight at preselected time points between embryonic days(E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg·kg^(-1). Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death.The Hedgehog(Hh) signalling pathway is essential for cellular proliferation and differentiation during embryonic development.Gain and loss of function of Hh signalling are known to result in an array of craniofacial malformations. To determine the critical period for Hh pathway antagonist-induced frontal bone hypoplasia, we examined patterns of dysmorphology caused by Hh signalling inhibition. Pregnant mice received a single oral administration of Hh signalling inhibitor GDC-0449 at 100 or 150 mg·kg^(-1) body weight at preselected time points between embryonic days(E)8.5 and 12.5. The optimal teratogenic concentration of GDC-0449 was determined to be 150 mg·kg^(-1). Exposure between E9.5 and E10.5 induced frontal bone dysplasia, micrognathia and limb defects, with administration at E10.5 producing the most pronounced effects. This model showed decreased ossification of the frontal bone with downregulation of Hh signalling. The osteoid thickness of the frontal bone was significantly reduced. The amount of neural crest-derived frontal bone primordium was reduced after GDC-0449 exposure owing to a decreased rate of cell proliferation and increased cell death.

关 键 词：GDC-0449 was determined PRIMORDIUM was REDUCED 

分 类 号：R[医药卫生]