Work

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

Year: 2019

Type: article

Abstract: 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. During embryonic development, the Hedgehog signalling pathway regulates the migration, proliferation and differentiation of cranial neural crest cells in the early frontal bone. The Hedgehog signalling pathway transmits information to embryonic cells for their proper cell differentiation, and increased or reduced function of that signalling results in various craniofacial malformations. A team headed by Weihui Chen at Fujian Medical University in China investigated the patterns of abnormalities caused by inhibition of Hedgehog signalling in pregnant mice at preselected embryonic time points. The team was able to identify the critical period for sensitivity to GDC-0449, a potent Hedgehog signalling inhibitor. The authors believe that their mouse model can be effective in further investigating the mechanisms of craniofacial malformations and will have a profound impact on identifying candidate human disease genes and associated environmental factors.

Source: International Journal of Oral Science

DOI: 10.1038/s41368-018-0040-z