Tbx1 is a negative modulator of Mef2c.

The developmental role of the T-box transcription factor Tbx1 is exquisitely dosage-sensitive. In this study, we performed a microarray-based transcriptome analysis of E9.5 embryo tissues across a previously generated Tbx1 mouse allelic series. This analysis identified several genes whose expression was affected by Tbx1 dosage. Interestingly, we found that the expression of the gene encoding the cardiogenic transcription factor Mef2c was negatively correlated to Tbx1 dosage. In vivo data revealed Mef2c up-regulation in the second heart field (SHF) of Tbx1 null mutant embryos compared with wild-type littermates at E9.5. Conversely, Mef2c expression was decreased in the SHF and in somites of Tbx1 gain-of-function mutants. These results are consistent with the described role of Tbx1 in suppressing cardiac progenitor cell differentiation and indicate also a negative effect of Tbx1 on Mef2c during skeletal muscle differentiation. We show that Tbx1 occupies conserved regulatory regions of the Mef2c locus, suggesting a direct effect on Mef2c transcription. However, we also show that Tbx1 interferes with the Gata4→ Mef2c regulatory pathway. Overall, our study uncovered a target of Tbx1 with critical developmental roles, so highlighting the power of the dosage gradient approach that we used.