Cardiac tissue-specific repression of CELF activity disrupts alternative splicing and causes cardiomyopathy

Area of Science:

• Molecular Biology
• Cardiovascular Biology
• RNA Biology

Background:

• The CELF (CUG- and ETR-3-like factor) family of RNA binding proteins plays a role in regulating alternative splicing.
• Alternative splicing is critical for cardiac development and function.

Purpose of the Study:

• To investigate the role of CELF protein activity in cardiac function and alternative splicing in vivo.
• To determine the consequences of impaired CELF activity on heart development and disease progression.

Main Methods:

• Generation of transgenic mice (MHC-CELFDelta) expressing a dominant-negative CELF protein in the heart.
• Analysis of cardiac phenotype, including hypertrophy, dilated cardiomyopathy, fibrosis, and cardiac dysfunction.
• Genetic rescue experiments by crossing MHC-CELFDelta mice with mice overexpressing CUG-BP1.

Main Results:

• MHC-CELFDelta mice developed cardiac hypertrophy, dilated cardiomyopathy, fibrosis, and premature death.
• Defects in alternative splicing were observed as early as 3 weeks after birth.
• A greater penetrance of cardiac phenotype was observed in female mice, suggesting sex-specific modulation.
• Overexpression of CUG-BP1 rescued splicing defects, cardiac hypertrophy, and improved survival.

Conclusions:

• CELF protein activity is essential for maintaining normal alternative splicing in the heart.
• Impaired CELF-mediated alternative splicing leads to cardiac dysfunction and disease.
• CELF proteins are critical regulators of cardiac homeostasis and represent potential therapeutic targets for heart disease.