Gestational inhibition of CSF1R signaling using PLX5622 drives musculoskeletal changes in postnatal offspring

ABSTRACT Despite our understanding of the musculoskeletal system under homeostatic conditions and during tissue remodeling, the interplay between muscle and bone development in response to gestational perturbations is less well understood. Here, we used the colony-stimulating factor-1 receptor (CSF1R) inhibitor PLX5622 to disrupt macrophage and osteoclast proliferation, differentiation, and survival during the embryonic period in order to study the impacts on craniofacial development using high-resolution microcomputed tomography (μCT). Cranioskeletal and mandibular size and shape were assessed using geometric morphometric (GM) analysis and dense correspondence analysis (DeCA), while contrast-enhanced μCT and DeCA were utilized to examine the consequences of prenatal CSF1R inhibition on P1 offspring musculature. Combined, we observed significant disruptions to cranioskeletal and mandibular morphologies, and notable changes in the shape of the muscles of mastication and tongue in newly born pups exposed to the CSF1R inhibitor PLX5622 in utero . By assessing the craniofacial skeleton and associated musculature at birth, we provide a more direct view of how inhibition of CSF1R signaling across embryogenesis contributes to changes in musculoskeletal development during periods of craniofacial morphogenesis.