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Cell Rep. 2019 Aug 27;28(9):2247-2255.e5. doi: 10.1016/j.celrep.2019.07.090.

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

Author information

1
Morgridge Institute for Research, Madison, WI 53715, USA. Electronic address: lchu@morgridge.org.
2
Morgridge Institute for Research, Madison, WI 53715, USA.
3
Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA.
4
Department of Biostatistics, University of Florida, Gainesville, FL 32603, USA.
5
Department of Statistics, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Biostatistics and Medical Informatics, University of Wisconsin-Madison, Madison, WI 53792, USA.
6
Morgridge Institute for Research, Madison, WI 53715, USA; Department of Cell and Regenerative Biology, University of Wisconsin-Madison, Madison, WI 53706, USA; Department of Molecular, Cellular, & Developmental Biology, University of California, Santa Barbara, Santa Barbara, CA 93117, USA. Electronic address: jthomson@morgridge.org.

Abstract

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.

KEYWORDS:

HES7; gene oscillation; human embryonic stem cells; segmentation clock; spondylocostal dysostosis

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