NFATc3 and NFATc4 are required for cardiac development and mitochondrial function

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Molecular Genetics

Background:

• Nuclear factor of activated T-cells (NFAT) transcription factors regulate gene expression and myocyte function in adult muscles.
• The role of NFATs in embryonic heart development is not well understood.

Purpose of the Study:

• To investigate the function of NFATc3 and NFATc4 in embryonic heart development using a mouse model.
• To determine the impact of NFAT loss on cardiac morphogenesis and mitochondrial function.

Main Methods:

• Generation of nfatc3-/-nfatc4-/- mice to study embryonic lethality and cardiac defects.
• Analysis of ventricular myocyte proliferation, mitochondrial ultrastructure, and respiratory chain enzyme activity.
• Rescue experiments using cardiac-specific expression of constitutively active NFATc4.

Main Results:

• nfatc3-/-nfatc4-/- mice exhibit embryonic lethality, thin ventricles, pericardial effusion, and reduced myocyte proliferation.
• Cardiac mitochondria show swelling and abnormal cristae, with decreased complex II and IV activity and reduced oxidative capacity.
• Rescue with NFATc4 preserves embryonic viability, myocyte proliferation, cardiac structure, and mitochondrial function.

Conclusions:

• NFATc3 and NFATc4 are crucial for embryonic heart development, particularly for mitochondrial energy metabolism.
• Loss of NFAT activity leads to metabolic failure, impacting cardiac morphogenesis.
• NFATs are essential regulators of cardiac mitochondrial function during embryogenesis.