Endodermal Sox17‐dependent pathways & cardiac specification

Abstract

ES cells are unlimited in the potential to generate multiple cell types for cardiac repair; they also offer a faithful model of embryogenesis for dissecting the signal pathways governing cardiac development. Using lentiviral delivery of shRNA, we established the requirement for an endoderm‐expressed Sry‐box containing protein, Sox17, for cardiac myocyte differentiation in ES cells, through cell non‐autonomous mechanisms. Sox17 functions subsequent to mesoderm formation but prior to induction of Mesp1 and Mesp2, bHLH transcription factors that share an indispensable function in forming cardiac mesoderm. Sox17 induction is dependent on both the canonical Wnts and the Nodal/Activin pathways. The canonical Wnts‐beta‐catenin pathway, however, is chiefly responsible for the induction of mesoderm and is suppressed during cardiac specification; Sox17 binds and suppresses beta‐catenin‐dependent transcription, thus plays a key role in the process. The Nodal/Activin‐Cripto pathway is more specific in inducing Sox17 and subsequent endodermal cardiac‐inducing signals, including Hhex and Cerberus. Nodal/Activin‐induced Hhex and Cerberus are dependent on Sox17; both play important roles in cardiac development in ES cells. Further depicting the endoderm cardiac‐inducing signals may guide toward more efficient cardiac myocyte differentiation in ES cells.