Figure 7.

The Sox17-Hhex-Cer1 pathway for heart induction in differentiating mouse embryonic stem cells (ESCs). Sox17 expression is contingent on input from β-catenin-dependent Wnts, BMPs, and Nodal. Its induction in the endoderm is mandatory for a cell nonautonomous signal (X) that activates Mesp1 and Mesp2, the essential first step directing the primitive mesoderm toward cardiac muscle specification (stages noted below the mesoderm compartment). Two Sox17-dependent endodermal genes, Hhex and Cer1, act in series downstream from Mesp1/2 to trigger the induction of cardiogenic transcription factors, such as Nkx2–5 and Tbx5, which denote and execute the cardiac muscle lineage decision. Sox17 activates Cer1 both directly, via sequence-specific binding and trans-activation, and indirectly, via Hhex. Forced expression of Cer1 can reduce the lack of cardiac muscle differentiation in Hhex-deficient ESCs.