[Hedgehog pathway antagonist-induced oromandibular limb hypogenesis in mouse]

Area of Science:

• Developmental biology
• Teratology
• Pharmacology

Background:

• The Hedgehog signaling pathway plays a crucial role in embryonic development.
• Understanding the teratogenic effects of pathway inhibitors is vital for drug safety and developmental research.

Purpose of the Study:

• To investigate the teratogenic effects of GDC-0449 on fetal development.
• To establish a mouse model of GDC-0449-induced oromandibular and limb hypogenesis for pathogenesis research.

Main Methods:

• Pregnant ICR mice were exposed to GDC-0449 at various embryonic days (E8.5-E15.5).
• Embryonic phenotypes were analyzed using stereo microscopy, histology, whole-mount skeletal staining, and micro-computed tomography.
• Optimal dysmorphogenic concentrations were determined.

Main Results:

• GDC-0449 exposure between E9.5-E10.5 resulted in craniofacial and limb malformations, including micrognathia, microglossia, ectrodactylia, partial anodontia, and cleft palate.
• Exposure on E11.5 and E12.5 led to a high incidence of cleft palate.
• The observed phenotypes closely resemble oromandibular limb hypogenesis syndrome.

Conclusions:

• GDC-0449 can induce specific birth defects such as micrognathia, microglossia, ectrodactylia, partial anodontia, and cleft palate.
• This study successfully established a novel mouse model for oromandibular limb hypogenesis.