PDF(Pubmed)
Abstract：
Mutations in the Chromodomain helicase DNA-binding protein 7 - coding gene (CHD7) cause CHARGE syndrome (CS). Although craniofacial and skeletal abnormalities are major features of CS patients, the role of CHD7 in bone and cartilage development remain largely unexplored. Here, using a zebrafish (Danio rerio) CS model, we show that chd7-/- larvae display abnormal craniofacial cartilage development and spinal deformities. The craniofacial and spine defects are accompanied by a marked reduction of bone mineralization. At the molecular level, we show that these phenotypes are associated with significant reduction in the expression levels of osteoblast differentiation markers. Additionally, we detected a marked depletion of collagen 2α1 in the cartilage of craniofacial regions and vertebrae, along with significantly reduced number of chondrocytes. Chondrogenesis defects are at least in part due to downregulation of htr2b, which we found to be also dysregulated in human cells derived from an individual with CHD7 mutation-positive CS. Overall, this study thus unveils an essential role for CHD7 in cartilage and bone development, with potential clinical relevance for the craniofacial defects associated with CS.
Patients with CHARGE syndrome exhibit skeletal defects. CHARGE syndrome is primarily caused by mutations in the chromatin remodeler-coding gene CHD7. To investigate the poorly characterized role of CHD7 in cartilage and bone development, here, we examine the craniofacial and bone anomalies in a zebrafish chd7-/- mutant model. We find that zebrafish mutant larvae exhibit striking dysmorphism of craniofacial structures and spinal deformities. Notably, we find a significant reduction in osteoblast, chondrocyte, and collagen matrix markers. This work provides important insights to improve our understanding of the role of chd7 in skeletal development.
Patients with CHARGE syndrome exhibit skeletal defects. CHARGE syndrome is primarily caused by mutations in the chromatin remodeler-coding gene CHD7. To investigate the poorly characterized role of CHD7 in cartilage and bone development, here, we examine the craniofacial and bone anomalies in a zebrafish chd7-/- mutant model. We find that zebrafish mutant larvae exhibit striking dysmorphism of craniofacial structures and spinal deformities. Notably, we find a significant reduction in osteoblast, chondrocyte, and collagen matrix markers. This work provides important insights to improve our understanding of the role of chd7 in skeletal development.
摘要：
染色体域解旋酶DNA结合蛋白7编码基因(CHD7)的突变引起CHARGE综合征(CS)。尽管颅面和骨骼异常是CS患者的主要特征，CHD7在骨和软骨发育中的作用在很大程度上仍未被探索.这里,使用斑马鱼（Daniorerio）CS模型，我们显示chd7-/-幼虫表现出异常的颅面软骨发育和脊柱畸形。颅面和脊柱缺损伴随着骨矿化的显着减少。在分子水平上,我们发现这些表型与成骨细胞分化标志物表达水平显著降低有关。此外,我们在颅面区域和椎骨的软骨中检测到胶原蛋白2α1的明显消耗，伴随着软骨细胞数量的显著减少。软骨形成缺陷至少部分是由于htr2b的下调，我们发现，在来自CHD7突变阳性CS个体的人体细胞中，这种情况也失调。总的来说,因此，这项研究揭示了CHD7在软骨和骨骼发育中的重要作用，与CS相关的颅面缺损具有潜在的临床相关性。
