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Stem Cells June 1, 2014; 32 (6): 1515-26.

Hhex and Cer1 mediate the Sox17 pathway for cardiac mesoderm formation in embryonic stem cells.

Liu Y , Kaneda R , Leja TW , Subkhankulova T , Tolmachov O , Minchiotti G , Schwartz RJ , Barahona M , Schneider MD .

Cardiac muscle differentiation in vivo is guided by sequential growth factor signals, including endoderm-derived diffusible factors, impinging on cardiogenic genes in the developing mesoderm. Previously, by RNA interference in AB2.2 mouse embryonic stem cells (mESCs), we identified the endodermal transcription factor Sox17 as essential for Mesp1 induction in primitive mesoderm and subsequent cardiac muscle differentiation. However, downstream effectors of Sox17 remained to be proven functionally. In this study, we used genome-wide profiling of Sox17-dependent genes in AB2.2 cells, RNA interference, chromatin immunoprecipitation, and luciferase reporter genes to dissect this pathway. Sox17 was required not only for Hhex (a second endodermal transcription factor) but also for Cer1, a growth factor inhibitor from endoderm that, like Hhex, controls mesoderm patterning in Xenopus toward a cardiac fate. Suppressing Hhex or Cer1 blocked cardiac myogenesis, although at a later stage than induction of Mesp1/2. Hhex was required but not sufficient for Cer1 expression. Over-expression of Sox17 induced endogenous Cer1 and sequence-specific transcription of a Cer1 reporter gene. Forced expression of Cer1 was sufficient to rescue cardiac differentiation in Hhex-deficient cells. Thus, Hhex and Cer1 are indispensable components of the Sox17 pathway for cardiopoiesis in mESCs, acting at a stage downstream from Mesp1/2.

PubMed ID: 24585688
PMC ID: PMC4260090
Article link: Stem Cells
Grant support: [+]

Species referenced: Xenopus laevis
Genes referenced: cer1 ctnnb1 foxa1 foxa2 hhex lgals4.2 mesp2 mespb myh6 nkx2-5 nodal nodal1 sox17a sox17b.1 tbx5 tbxt tdgf1.3

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References [+] :
Alexander, casanova plays an early and essential role in endoderm formation in zebrafish. 1999, Pubmed, Xenbase