Genetic interaction of <em>Thm2</em> and <em>Thm1</em> Shapes Postnatal Craniofacial Bone

Abstract

Ciliopathies are genetic syndromes that link skeletal dysplasias to dysfunction of primary cilia. Primary cilia are sensory organelles synthesized by intraflagellar transport (IFT) - A and B complexes, which traffic protein cargo along a microtubular core. We have reported that deletion of IFT-A gene, Thm2, together with a null allele of its paralog, Thm1, causes a small skeleton with small mandible or micrognathia in juvenile mice. Using micro-computed tomography, here we quantify the craniofacial defects of Thm2-/-;Thm1aln/- triple allele mutant mice. At postnatal day 14, triple allele mutant mice exhibit micrognathia, maxillary hypoplasia, and a decreased facial angle due to shortened maxilla, premaxilla, and nasal bones, reflecting altered development of facial anterior-posterior elements. In contrast, other ciliopathy-related craniofacial defects, such as cleft lip and/or palate, hypo-/hypertelorism, broad nasal bridge, craniosynostosis, and facial asymmetry, were not observed, suggesting development of the facial transverse dimension is intact. Calvarial-derived osteoblasts of triple allele mutant mice showed reduced bone formation in vitro that was ameliorated by Hedgehog agonist, SAG. Together, these data indicate that Thm2 and Thm1 genetically interact to regulate bone formation and sculpting of the postnatal face. The triple allele mutant mice present as a novel model to study craniofacial bone development.