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Session: Developmental Biology Award Hybrid Symposium

Cranial Cartilage Defects in the Fgfr3Y367C/+ Mouse Model of Achondroplasia

Monday, March 27, 2023
9:00 AM – 9:15 AM US EST
Room: Grand Ballroom Salon I
Abstract Body : Achondroplasia, the most common primary skeletal dysplasia in humans, is caused by one of two possible point mutations of the transmembrane portion of fibroblast growth factor receptor 3 (FGFR3) leading to a gain of function mechanism of FGFR3 and subsequent growth plate and cartilage 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 primarily defined based on postnatal effects on bone and cartilage, and embryonic development of tissues in affected individuals is not well studied. Using the Fgfr3Y367C/+ mouse model of 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 cartilages, which in turn can secondarily affect cranial 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 to JR and the University of Bordeaux Initiative of Excellence (IdEx Bordeaux) to JR and YH.