Rdh10 loss-of-function and perturbed retinoid signaling underlies the etiology of choanal atresia

• Published in: Human molecular genetics Vol. 26; no. 7; pp. 1268 - 1279
• Main Authors: Kurosaka, Hiroshi, Wang, Qi, Sandell, Lisa, Yamashiro, Takashi, Trainor, Paul A
• Format: Journal Article
• Language: English
• Published: England Oxford University Press 01-04-2017
• Subjects: Alcohol Oxidoreductases - biosynthesis; Alcohol Oxidoreductases - genetics; Animals; Choanal Atresia - genetics; Choanal Atresia - metabolism; Choanal Atresia - physiopathology; Disease Models, Animal; Embryonic Development - genetics; Face - physiopathology; Fibroblast Growth Factor 8 - genetics; Gene Expression Regulation, Developmental; Humans; Maxillofacial Development - genetics; Mice; Morphogenesis - genetics; Mutation; Vitamin A - genetics; Vitamin A - metabolism
• ISSN: 0964-6906; 1460-2083
• DOI: 10.1093/hmg/ddx031

Craniofacial development is a complex process that involves sequential growth and fusion of the facial prominences. When these processes fail, congenital craniofacial anomalies can occur. For example, choanal atresia (CA) is a congenital craniofacial anomaly in which the connection between the nasal airway and nasopharynx is completely blocked. CA occurs in approximately 1/5000 live births and is a frequent component of congenital disorders such as CHARGE, Treacher Collins, Crouzon and Pfeiffer syndromes. However, the detailed cellular and molecular mechanisms underpinning the etiology and pathogenesis of CA remain elusive. In this study, we discovered that mice with mutations in retinol dehydrogenase 10 (Rdh10), which perturbs Vitamin A metabolism and retinoid signaling, exhibit fully penetrant CA. Interestingly, we demonstrate Rdh10 is specifically required in non-neural crest cells prior to E10.5 for proper choanae formation, and that in the absence of Rdh10, Fgf8 is ectopically expressed in the nasal fin. Furthermore, we found that defects in choanae development are associated with decreased cell proliferation and increased cell death in the epithelium of the developing nasal cavity, which retards invagination of the nasal cavity, and thus appears to contribute to the pathogenesis of CA. Taken together, our findings demonstrate that RDH10 is essential during the early stages of facial morphogenesis for the formation of a functional nasal airway, and furthermore establish Rdh10 mutant mice as an important model system to study CA.