| Abstract | Achondroplasia, the most common chondrodysplasia in humans, is caused by one gain of function mutation localized in the transmembrane domain of fibroblast growth factor receptor 3 (FGFR3) leading to a FGFR3 constitutive activation and subsequent growth plate cartilage and bone defects. Phenotypic features of achondroplasia include macrocephaly with frontal bossing, midface hypoplasia, disproportionate shortening of the extremities, brachydactyly with trident configuration of the hand, and bowed legs. The condition is defined primarily on postnatal effects on bone and cartilage, and embryonic development of tissues in affected individuals is not well studied. Using the Fgfr3Y367C/+ mouse model mimicking achondroplasia, we investigated the developing chondrocranium and Meckel’s cartilage (MC) at embryonic day (E)14.5 and E16.5. Sparse hand annotations of chondrocranial and MC cartilages visualized in phosphotungstic acid enhanced three-dimensional (3D) micro-computed tomography images were used to train our automatic deep learning-based 3D segmentation model and produce 3D isosurfaces of the chondrocranium and MC. Using linear distances estimated from 3D coordinates of landmarks measured on the 3D isosurfaces, we quantified differences in the chondrocranium and MC of Fgfr3Y367C/+ mice relative to that of their unaffected littermates. Statistically significant differences in morphology and growth of the chondrocranium and MC were found, indicating direct effects of this Fgfr3 mutation on embryonic cranial and pharyngeal cartilages, which in turn can secondarily affect cranial and pharyngeal dermal bone development. Our results support the suggestion that early therapeutic intervention during cartilage formation may lessen the effects of this condition.
Grant support. This work was supported in part by NIH/NICDR grants R01 DE027677, R01 DE031439, and R01 DE 029832 to JTR and the University of Bordeaux Initiative of Excellence (IdEx Bordeaux) to JTR and YH.
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