生物
肢体发育
骨形态发生蛋白
软骨发生
细胞生物学
前肢
形态发生
遗传学
胚胎
解剖
干细胞
基因
作者
Tingting Yu,Guoqiang Li,Chen Wang,Li Niu,Rutao Yao,Jian Wang
摘要
Multiple synostoses syndromes (SYNS) are a group of rare genetic bone disorders characterized by multiple joint fusions. We previously reported an SYNS4-causing GDF6 c.1330 T > A (p.Tyr444Asn) mutation, which reduced Noggin-induced GDF6 inhibition and enhanced SMAD1/5/8 signaling. However, the mechanisms by which GDF6 gain-of-function mutation alters joint formation and the comprehensive molecular portraits of SYNS4 remain unclear. Herein, we introduce the p.Tyr443Asn (orthologous to the human GDF6 p.Tyr444Asn) mutation into the mouse Gdf6 locus and report the results of extensive phenotype analysis, joint development investigation, and transcriptome profiling of Gdf6 p.Tyr443Asn limb buds. Gdf6 p.Tyr443Asn knock-in mice recapitulated the morphological features of human SYNS4, showing joint fusion in the wrists, ankles, phalanges, and auditory ossicles. Analysis of mouse embryonic forelimbs demonstrated joint interzone formation defects and excess chondrogenesis in Gdf6 p.Tyr443Asn knock-in mice. Further, RNA sequencing of forelimb buds revealed enhanced bone formation and upregulated bone morphogenetic protein (BMP) signaling in mice carrying the Gdf6 p.Tyr443Asn mutation. Because tightly regulated BMP signaling is critical for skeletal development and joint morphogenesis, our study shows that enhancing GDF6 activity has a significant impact on both prenatal joint development and postnatal joint maintenance. © 2023 American Society for Bone and Mineral Research (ASBMR).
科研通智能强力驱动
Strongly Powered by AbleSci AI