Morgridge Institute for Research, Madison, WI 53715, USA.
Morgridge Institute for Research, Madison, WI 53715, USA.
Cell Rep. 2019 Aug 27;28(9):2247-2255.e5. doi: 10.1016/j.celrep.2019.07.090.
Defects in somitogenesis result in vertebral malformations at birth known as spondylocostal dysostosis (SCDO). Somites are formed with a species-specific periodicity controlled by the "segmentation clock," which comprises a group of oscillatory genes in the presomitic mesoderm. Here, we report that a segmentation clock model derived from human embryonic stem cells shows many hallmarks of the mammalian segmentation clock in vivo, including a dependence on the NOTCH and WNT signaling pathways. The gene expression oscillations are highly synchronized, displaying a periodicity specific to the human clock. Introduction of a point of mutation into HES7, a specific mutation previously associated with clinical SCDO, eliminated clock gene oscillations, successfully reproducing the defects in the segmentation clock. Thus, we provide a model for studying the previously inaccessible human segmentation clock to better understand the mechanisms contributing to congenital skeletal defects.
体节形成缺陷导致出生时出现椎体畸形，称为脊椎体肋发育不良（SCDO）。体节的形成具有物种特异性的周期性，由前体节中一组振荡基因控制，称为“体节时钟”。在这里，我们报告说，源自人类胚胎干细胞的体节时钟模型显示出许多体内哺乳动物体节时钟的特征，包括对 NOTCH 和 WNT 信号通路的依赖性。基因表达振荡高度同步，显示出与人时钟特定的周期性。将先前与临床 SCDO 相关的特定突变 HES7 中的一个点突变引入其中，消除了时钟基因的振荡，成功复制了体节时钟的缺陷。因此，我们提供了一个研究以前无法获得的人类体节时钟的模型，以更好地了解导致先天性骨骼缺陷的机制。
