Murine Creld1 controls cardiac development through activation of calcineurin/NFATc1 signaling

Abstract

Calcineurin is a heteromeric Ca(2+)-dependent serine/threonine phosphatase. It dephosphorylates the transcription factor nuclear factor of activated T cells (NFAT) in the cytoplasm, which subsequently undergoes nuclear translocation. NFAT regulates numerous biological processes, including inflammatory T cell responses and cardiac development. Our study identifies the Cysteine-Rich with EGF-Like Domains 1 (Creld1) gene as a regulator of calcineurin/NFATc1 signaling. We show that Creld1 is sufficient to promote NFATc1 dephosphorylation and translocation to the nucleus. Creld1 is contained in a joint protein complex with the regulatory subunit of calcineurin, CnB, thereby controlling calcineurin function. Localization of Creld1 at the endoplasmic reticulum (ER) is important to exert its action on calcineurin. By using Creld1KO mice, we demonstrate that Creld1 is essential for heart development. Creld1 function is required for the VEGF-dependent proliferation of endocardial cells by promoting the expression of NFATc1 target-genes. Collectively, our study identifies Creld1 as an important regulator of calcineurin/NFATc1 signaling.