Klf6 is a zinc finger transcription factor that has been identified as a tumor suppressor gene inactivated in several human cancers. We previously reported that Klf6^-/- mice are embryonic lethal because of impaired hematopoietic differentiation. In that study, we also found Klf6^-/- mice have undefinable livers. Combined with this observation and its developmental expression pattern, Klf6 might have a role in in differentiation of non-hematopoietictissues. The aim of this study was to more clearly define the roles of Klf6 in tissue specification using tissue-specific ES cell differentiation systems. We have evaluated three different culture conditions to induce ES cell differentiation, comparing the responses between Klf6^+/+ and Klf6^-/- ES cells. Neuronal differentiation of Klf6^-/- ES cells was impaired based on marker gene expression and morphology. Interestingly, Klf6 ^-/- ES cells began to express Hnf3β mRNA, which identified these cells as endodermal precursors, suggesting that Klf6 ordinarily suppresses endoderm differentiation in this culture condition. Additionally, when Klf6^-/- ES cells were grown in StemPro34 serum free medium, they showed enhanced cardiac differentiation to a greater extent than Klf6^+/+ ES cells, suggesting that Klf6 may have an inhibitory activity in preventing cardiomyogenesis. These findings indicate divergent and tissue- specific roles of Klf6 in ES cell differentiation.

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