Gene‐Environment Interaction between Twist and Thyroid Hormone Results in Extreme Craniosynostotic Phenotypes in Mice

Abstract

Craniosynostosis (CS) is the premature fusion of one or more cranial sutures; it can both hinder the growth of the brain and result in severe craniofacial dysmorphology. Although several genes have been implicated with CS, it is unclear how these genotypes lead to widely variable phenotypes. One possibility is gene‐environment interaction. A CDC study found several environmental risk factors associated CS, including maternal hyperthyroidism. We hypothesize that predisposed genotypes will result in more extreme CS phenotypes when exposed to thyroid hormone. To test this we introduced thyroxine to the maternal environment of a genetic CS mouse model, Twist+/−. TWIST has been linked with CS and this model exhibits variable phenotypic expression of CS. Twist+/− and WT control pregnant dams were given thyroxine‐laced water at E13, before suture formation. We sacrificed neonates at P15 and scanned the skulls using μCT. We collected landmarks from the 3D reconstructions and analyzed them using geometric morphometrics. Our preliminary results show that thyroxine has a clear affect on the shape of both Twist+/− and WT skulls and it affects the two groups differently. Exposed Twist+/− mice have higher cranial vaults, wider calvaria, shorter maxilla lengths and wider midfaces compared to both WT and Twist+/− unexposed mice; these shape changes are similar to those associated with CS.Grant Funding Source: Cleft Palate Foundation