Host: The Japanese Society of Toxicology
Name : The 49th Annual Meeting of the Japanese Society of Toxicology
Date : June 30, 2022 - July 02, 2022
Midline facial defects are highly most common birth defects and the midfacial cleft (MFC) is one of the most severe forms. During development, cranial neural crest cells (CNCCs) migrate to populate nasal processes, where they contribute to form midline facial structures. Here we identified a small increase of Bone Morphogenetic Protein (BMP) signaling via one of the BMP receptors ACVR1 with a constitutively activated mutation (ca-Acvr1) induces multi-level metabolic and epigenetic remodeling in cranial neural crest cells (CNCCs) thus causing midfacial defects, including (MFC).
The mutant embryos started to show abnormal facial morphology at embryonic day 10.5 (E10.5). They developed an enlarged midfacial structure with abnormal medial nasal and lateral nasal processes leading to MFC. Unbiased gene expression analyses revealed that an increase of Aryl hydrocarbon receptor (AHR) in the mutant embryos. Interestingly, administration of alpha-naphthoflavon, an antagonist for AHR signaling, restored normal facial development in the half of the mutant embryos. By a similar approach to enhance BMP signaling using another type 1 BMP receptor (ca-Bmpr1a), the resulting mutant mice did not develop MFC, however, administration of sub-optical does of beta-naphthoflavon, an agonist for AHR signaling, resulted in MFC only in the mutant embryos. These facts suggest that AHR signaling activity is positively regulated by BMP signaling and this may be one of the mechanisms of facial anomalies caused by increased BMP signaling. These also suggest that levels of BMP signaling may act as a risk factor for environmental insults.
