Spatial Multiomics Reveal the Role of Wnt Modulator, Dkk2, in Palatogenesis.

Multiple genetic and environmental etiologies contribute to the pathogenesis of cleft palate, which constitutes the most common among the inherited disorders of the craniofacial complex. Insights into the molecular mechanisms regulating osteogenic differentiation and patterning in the palate during embryogenesis are limited and needed for the development of innovative diagnostics and cures. This study utilized the mouse model with a consistent phenotype of cleft secondary palate to investigate the role of in the process of palatal osteogenesis. While prior research had identified upregulation of Wnt pathway modulators and in palate mesenchyme, limitations of spatial resolution and technology restricted a more robust analysis. Here, data from single-nucleus transcriptomics and chromatin accessibility assays validated by highly multiplex targeted single-cell spatial profiling technology suggest a distinct relationship between and osteogenic populations. Loss of results in spatially restricted osteogenic domains bounded by , which normally interfaces with in the mesenchyme. These results suggest that Pax9-dependent Wnt signaling modulators influence osteogenic programming during palate formation, potentially contributing to the observed cleft palate phenotype.