An In Vitro Human Segmentation Clock Model Derived from Embryonic Stem Cells
An In Vitro Human Segmentation Clock Model Derived from Embryonic Stem Cells
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DOI：
10.1016/j.celrep.2019.07.090
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发表时间：
2019-08-27
期刊：
影响因子：
8.8
通讯作者：
Thomson, James A.
中科院分区：
文献类型：
--
作者：
Chu, Li-Fang;Mamott, Daniel;Thomson, James A.
体节发育缺陷导致出生时的脊椎畸形，称为脊椎肋骨发育不全（SCDO）。体节的形成具有种特异性的周期性，由“体节时钟”控制，体节时钟包括一组位于体前中胚层的振荡基因。在这里，我们报告说，来自人类胚胎干细胞的分割时钟模型显示了许多特点的哺乳动物体内分割时钟，包括依赖于NOTCH和WNT信号通路。基因表达振荡是高度同步的，显示出人类生物钟特有的周期性。将突变点引入HES7（先前与临床SCDO相关的特定突变）消除了时钟基因振荡，成功地再现了分段时钟中的缺陷。因此，我们提供了一个模型，用于研究以前无法访问的人类分割时钟，以更好地了解导致先天性骨骼缺陷的机制。
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.