Wnt5a gain- and loss-of-function present distinctly in craniofacial bone.

Introduction: Robinow syndrome has characteristic craniofacial and dental features and can be caused by gain- or loss-of-function variants in Wnt family member 5A () non-canonical signaling. The craniofacial and dental manifestation of Robinow syndrome is heterogenous, as is the effect of altered in animal models. The relationship between and craniofacial and dental phenotypes is not fully understood.

Methods: To investigate the role of in craniofacial and dental development, we utilized a conditional loss-of-function (LOF: ) and a conditional gain-of-function (GOF: model to determine the effect of both LOF and GOF of in bone cells during craniofacial and dental development. Postnatal day 10 conditional LOF , GOF , and control skulls were scanned by micro-computed tomography and assessed using traditional and geometric morphometrics. Mandibular bone apoptosis was further assessed by TUNEL staining.

Results: Conditional LOF resulted in midface hypoplasia, increased maxillary intermolar width, increased rostral basisphenoid width, and delayed molar eruption. LOF mandibles did not have altered bone mineral density or bone microarchitecture unlike our previous study examining LOF femurs. In contrast, conditional GOF results in macrocephaly, shortened hard palate, increased zygomatic length, micrognathia, and mandibular process morphology changes. The micrognathia and mandibular process morphology changes in the GOF mice were not due to increased apoptosis. A partially penetrant snout deviation was present in both the LOF and GOF mice.

Conclusions: Craniofacial and dental phenotype differed between mice with conditional GOF and LOF of , consistent with the craniofacial phenotype heterogeneity in -associated Robinow syndrome. We detected tooth eruption delay, mandibular condyle dysmorphology, and facial asymmetry in mice with altered that have not been previously reported in patients. Our data suggest precise regulation of is essential for proper craniofacial and dental development.