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 mg•kg⁻¹ 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.

刺猬（Hh）信号通路对于胚胎发育过程中的细胞增殖和分化至关重要。已知Hh信号功能的获得和丧失会导致一系列颅面畸形。为了确定Hh途径拮抗剂引起的额骨发育不全的关键时期，我们检查了由Hh信号抑制引起的畸形的模式。怀孕的小鼠在胚胎天（E）8.5至12.5之间的预先选择的时间点接受了100 mg•kg ^{- 1}或150mg•kg ^{- 1}体重的Hh信号抑制剂GDC-0449的单次口服给药。确定GDC-0449的最佳致畸浓度为150 mg•kg ^{− 1}。E9.5和E10.5之间的暴露会引起额骨发育异常，微棘痛和肢体缺损，以E10.5施用会产生最明显的影响。该模型显示，Hh信号的下调会降低额骨的骨化。额骨的类骨质厚度明显减少。GDC-0449暴露后，神经c衍生的额骨原基的数量减少，这是由于细胞增殖速率降低和细胞死亡增加所致。