Mutations in the gene encoding the gap-junctional
protein connexin43 (
Cx43) are the cause of the human disease
oculodentodigital dysplasia (
ODDD). The mandible is often affected in this disease, with clinical reports describing both mandibular overgrowth and conversely,
retrognathia. These seemingly opposing observations underscore our relative lack of understanding of how
ODDD affects mandibular morphology. Using two mutant mouse models that mimic the
ODDD phenotype (I130T/+ and G60S/+), we sought to uncover how altered
Cx43 function may affect mandibular development. Specifically, mandibles of newborn mice were imaged using micro-CT, to enable statistical comparisons of shape. Tissue-level comparisons of key regions of the mandible were conducted using histomorphology, and we quantified the
mRNA expression of several cartilage and bone cell differentiation markers. Both G60S/+ and I130T/+ mutant mice had altered mandibular morphology compared to their wildtype counterparts, and the morphological effects were similarly localized for both mutants. Specifically, the biggest phenotypic differences in mutant mice were focused in regions exposed to mechanical forces, such as alveolar bone, muscular attachment sites, and articular surfaces. Histological analyses revealed differences in ossification of the intramembranous bone of the mandibles of both mutant mice compared to their wildtype littermates. However, chondrocyte organization within the secondary cartilages of the mandible was unaffected in the mutant mice. Overall, our results suggest that the morphological differences seen in G60S/+ and I130T/+ mouse mandibles are due to delayed ossification and suggest that mechanical forces may exacerbate the effects of
ODDD on the skeleton.