CELF-mediated alternative splicing is required for cardiac function during early, but not later, postnatal life

Abstract 

During the transition from juvenile to adult life, the heart undergoes programmed remodeling at the levels of transcription and alternative splicing. Members of the CUG-BP and ETR-3-like factor (CELF) family have been implicated in driving developmental transitions in alternative splicing of cardiac transcripts during maturation of the heart. Here, we investigated the timing of the requirement for CELF activity in the postnatal heart using a previously described transgenic mouse model (MHC-CELFΔ). In MHC-CELFΔ mice, nuclear CELF activity has been disrupted specifically in the heart by cardiac-specific expression of a dominant negative CELF protein. Longitudinal analyses of two lines of MHC-CELFΔ mice with differing levels of dominant negative protein expression demonstrate that CELF splicing activity is required for healthy cardiac function during juvenile, but not adult, life. Cardiac function, chamber dilation, and heart size all recover with age in the mild line of MHC-CELFΔ mice without a loss of dominant negative protein expression or change in expression of endogenous CELF proteins or known CELF antagonists. This is the first example of a mouse model with genetically induced cardiomyopathy that spontaneously recovers without intervention. Our results suggest that CELF proteins are key players in the integrated gene expression program involved in postnatal cardiac remodeling and maturation.

Abbreviations: CUG-BP1, CUG binding protein 1, ETR-3, ELAV-type RNA binding protein 3, CELF, CUG-BP and ETR-3-like factor, MHC, myosin heavy chain, cTNT, cardiac troponin T, CaMK, Ca²⁺/calmodulin-dependent kinase, LVESD, left ventricular end systolic dimension, PWS, posterior wall thickness during systole, MBNL, muscleblind-like, Mtmr1, myotubularin related protein 1, Bin1, bridging integrator 1, Mef2A, myocyte enhancer factor 2A

Keywords: Alternative splicing, CELF proteins, Transgenic mice, Cardiomyopathy, Development, Postnatal remodeling