An In Vitro Human Segmentation Clock Model Derived from Embryonic Stem Cells

Abstract

Summary: 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. : The segmentation clock is a molecular oscillator regulating the tempo of somite formation in a species-specific manner. Chu et al. report an embryonic-stem-cell-derived model system displaying a human-specific gene oscillation periodicity, which can shed light on human somitogenesis and model skeletal developmental disorders. Keywords: human embryonic stem cells, segmentation clock, HES7, gene oscillation, spondylocostal dysostosis