Transient HES5 Activity Instructs Mesodermal Cells toward a Cardiac Fate

• DOI: 10.1016/j.stemcr.2017.05.025
• Publication Date: 2017-06-22T21:03:29Z
• Authors: Ana G. Freire; Avinash Waghray; Francisca Soares-...; Tatiana P. Resende; Dung-Fang Lee; Carlos-Filipe Per...; Diana S. Nascimento; Ihor R. Lemischka; Perpétua Pinto-do-Ó
• Keywords: 0301 basic medicine; Medicine (General); QH301-705.5; notch signaling pathway; Article; Cell Line; Mesoderm; Mice; 03 medical and health sciences; R5-920; Basic Helix-Loop-Helix Transcription Factors; Animals; Erythropoiesis; Myocytes, Cardiac; Biology (General); Cell Proliferation; Gastrulation; Gene Expression Regulation, Developmental; Cell Differentiation; Mouse Embryonic Stem Cells; Repressor Proteins; nascent mesoderm; Gene Knockdown Techniques; cardiac fate specification; Hes5; Signal Transduction

Notch signaling plays a role in specifying a cardiac fate but the downstream effectors remain unknown. In this study we implicate the Notch downstream effector HES5 in cardiogenesis. We show transient Hes5 expression in early mesoderm of gastrulating embryos and demonstrate, by loss and gain-of-function experiments in mouse embryonic stem cells, that HES5 favors cardiac over primitive erythroid fate. Hes5 overexpression promotes upregulation of the cardiac gene Isl1, while the hematopoietic regulator Scl is downregulated. Moreover, whereas a pulse of Hes5 instructs cardiac commitment, sustained expression after lineage specification impairs progression of differentiation to contracting cardiomyocytes. These findings establish a role for HES5 in cardiogenesis and provide insights into the early cardiac molecular network.