The RNA-binding protein SRSF3 controls epicardial formation by regulating splicing and proliferation

Area of Science:

• Cardiovascular Biology
• Developmental Biology
• Molecular Biology

Background:

• The epicardium plays a vital role in heart development and regeneration.
• Key molecular mechanisms governing epicardial formation remain incompletely understood.

Purpose of the Study:

• To investigate the role of the RNA-binding protein SRSF3 in epicardial formation and function.
• To elucidate the molecular mechanisms underlying SRSF3's regulation of epicardial development.

Main Methods:

• Utilized murine models with targeted Srsf3 deletion in the proepicardium.
• Employed single-cell RNA-sequencing to analyze cellular responses to Srsf3 depletion.
• Performed endogenous irCLIP to map SRSF3-RNA interactions.

Main Results:

• Srsf3 deletion in murine proepicardium caused proliferative arrest and impaired epicardial formation.
• Srsf3 depletion led to reduced epicardial proliferation and epicardium-derived cell (EPDC) formation.
• SRSF3 binds to cell cycle regulators Ccnd1 and Map4k4, influencing both splicing and non-splicing functions.

Conclusions:

• SRSF3 is essential for controlling epicardial proliferation and ensuring proper epicardial formation.
• SRSF3 regulates cardiac development through both splicing-dependent and independent mechanisms.
• Mosaic recombination can significantly confound embryonic phenotyping, underscoring the importance of SRSF3's regulatory role.