Communication between cardiomyocytes and non-myocyte cells is essential for heart development. In this study, Glenn Fishman and colleagues uncover a non-cell-autonomous role of the transcription factor early B-cell factor 1 (EBF1) in heart development. First, the authors find that Ebf1-deficient postnatal hearts in mice have abnormal heart structure, increased cardiomyocyte number and persistent cardiomyocyte proliferation. They also observe aberrant patterning and functioning of the ventricular conduction system - a group of specialised cardiomyocytes that coordinate heart contraction. To explore the basis of the observed phenotypes in postnatal Ebf1 knockout hearts, the authors study embryonic hearts and find developmental defects in cardiomyocyte proliferation and heart muscle maturation. Unexpectedly, the authors observe no EBF1 expression in cardiomyocytes of developing and postnatal hearts. Instead, EBF1 is expressed exclusively in non-myocyte cells, suggesting the observed Ebf1 knockout defects are likely caused by a non-cell-autonomous mechanism. Furthermore, to identify potential mechanisms for the hyperproliferative phenotype, the authors perform transcriptional profiling and observe enrichment of MYC targets in Ebf1-deficient cardiomyocytes. Finally, the authors find that BMP signalling induces Ebf1 expression in embryonic heart cultures, suggesting the existence of a feedback mechanism to counter the direct effects of BMPs on cardiomyocyte proliferation. Overall, the findings suggest EBF1 regulates heart development in a non-cell-autonomous manner.
