Learning skeletal development from genetic diseases
发布时间 :2018-04-24  阅读次数 :4413

报告题目:Learning skeletal development from genetic diseases

报告人:Yingzi Yang(Professor, Dept. of Developmental Biology, Harvard School of Dental Medicine & Harvard Stem Cell Institute)
联系人:解丛君  xiecongjun@sjtu.edu.cn



How osteoblast cells are induced during bone development is a central question for understanding the organizational principles underpinning a functional skeletal system. Abnormal osteoblast differentiation leads to a broad range of devastating diseases such as craniosynostosis (premature suture fusion), heterotopic ossification (HO) and osteoporosis. Molecular analyses of skeletal genetic diseases with abnormal osteoblast differentiation have provided important insights in the regulation of osteoblast induction. Progressive osseous heteroplasia (POH) (OMIM#166350) and Albright's hereditary osteodystrophy (AHO, OMIM 103580) are caused by loss function mutations in the GNAS gene, which encodes the stimulatory alpha subunit, Gαs, of heterotrimeric G protein that transduces signals from G protein coupled receptors (GPCRs). POH and AHO are characterized by progressive extra-skeletal bone formation through an intramembranous process. We have demonstrated that Gαs restricts bone formation to the skeleton by inhibiting Hedgehog (Hh) signaling in mesenchymal progenitor cells. In contrast, activating mutations of GNAS in McCune-Albright Syndrome (MAS) causes fibrous dysplasia (FD) (OMIM# 174800) characterized by reduced ossification and bone marrow fibrosis. Studies of both POH and FD have identified the novel roles of GPCR/ Gαs signaling in inhibiting Hedgehog (Hh) signaling while enhancing Wnt/beta-catenin signaling in the regulation of osteoblast differentiation from mesenchymal progenitors. Further, we found Gs signaling plays important roles in normal craniofacial development and s both AHO and FD patients exhibit severe cranial bone defects. Our work shows that studies of genetic diseases provide invaluable insights in normal bone development and understanding both leads to better diagnosis and therapeutic treatment of bone diseases.