Calreticulin secures calcium-dependent nuclear pore competency required for cardiogenesis

Area of Science:

• Cardiovascular Biology
• Cellular Biology
• Developmental Biology

Background:

• Calreticulin deficiency leads to embryonic lethal myocardial defects.
• Loss of calreticulin is linked to myofibrillogenesis failure via an unknown mechanism.
• Understanding calreticulin's role in cardiac development is crucial.

Purpose of the Study:

• To identify cellular processes disrupted by calreticulin deficiency.
• To elucidate the mechanism linking calreticulin deficit to cardiac myofibrillogenesis dysregulation.
• To investigate calreticulin's role in the acquisition of cardiac phenotype.

Main Methods:

• Utilized an embryonic stem cell knockout model for calreticulin deficit (crt(-/-)).
• Analyzed nucleocytoplasmic transport pathways and nuclear import of MEF2C.
• Examined nucleoporin and nuclear transport protein expression in crt(-/-) cardiomyocytes.
• Investigated the effect of ionophore treatment on nuclear pore structure and function.

Main Results:

• Calreticulin deficit compromised nucleocytoplasmic transport, disrupting MEF2C nuclear import.
• crt(-/-) cardiomyocytes exhibited abnormal nuclear pore complex (NPC) configuration with reduced pore diameter.
• Ionophore treatment corrected NPC microarchitecture, rescued nuclear import, and normalized myofibrillogenesis.

Conclusions:

• Calreticulin deficiency alters nuclear pore function and structure, impeding cardiac myofibrillogenesis.
• This disruption occurs through a calcium-dependent mechanism.
• Calreticulin is essential for nucleocytoplasmic communication, vital for proper cardiac development.