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Embryonic stem cells (ESCs) have the ability to proliferate indefinitely in culture, and to differentiate into all embryonic lineages. Although the transcriptional program that coordinates pluripotency has been progressively unveiled during the past few years, the signalling pathways that regulate early differentiation events are not completely understood. We have recently described that CnAbeta1, an alternative splicing variant of the phosphatase calcineurin, enhances muscle regeneration and improves cardiac function after myocardial infarction. CnAbeta1 lacks the autoinhibitory domain typical of calcineurin, and instead has a unique C-terminal domain with no similarity to any known protein. Unlike other calcineurin isoforms, CnAbeta1 has no impact on NFAT-regulated genes and instead activates the Akt pathway. CnAbeta1 is strongly expressed in stem and progenitor cells, although its role in these cells is unknown. We found that CnAbeta1 downregulation had no effect on ESC pluripotency. However, CnAbeta1 depletion in mESCs during the first 48 hours of differentiation specifically affected differentiation towards the cardiac mesoderm lineage promoting hematopoietic differentiation. In contrast, CnAbeta1 1 overexpression promoted cardiac differentiation. Our results suggest that CnAbeta1 1 regulates mESC differentiation through the control of the Akt/GSK3 signalling pathway.To determine the role of CnAbeta1 in the adult heart, we developed cardiac-specific CnAbeta1 transgenic mice overexpressing CnAbeta1 specifically in cardiomyocytes and CnAbeta1Δi12 knockout mice that lack CnAbeta1's unique C-terminal domain. We found that CnAbeta1Δi12 mice show increased cardiac hypertrophy in response to trans-aortic banding, whereas transgenic mice overexpressing CnAbeta1 have decreased hypertrophy and fibrosis, and improved cardiac function. Together, these results suggest that CnAbeta1 is implicated in early cardiac differentiation, and that it reduces pathological cardiac hypertrophy in the adult heart. [ABSTRACT FROM PUBLISHER]