Nucleo-cytoplasmic shuttling of splicing factor SRSF1 is required for development and cilia function

Area of Science:

• Molecular Biology
• Genetics
• Developmental Biology

Background:

• SRSF1 is an RNA-binding protein that shuttles between the nucleus and cytoplasm.
• Its role in post-splicing processes and physiological significance are not fully understood.

Purpose of the Study:

• To investigate the physiological role of SRSF1 shuttling using a novel mouse model.
• To determine the impact of nuclear-restricted SRSF1 on gene expression and cellular functions.

Main Methods:

• Genome editing was used to create a mouse model with SRSF1 retained in the nucleus (Srsf1NRS/NRS).
• Phenotypic analysis, including body size, hydrocephalus, and sperm motility, was performed.
• mRNA translation, protein abundance, and ciliary structure/motility were assessed.

Main Results:

• Srsf1NRS/NRS mice exhibited small body size, hydrocephalus, and immotile sperm, indicative of ciliary defects.
• Reduced translation of specific mRNAs and decreased levels of multiciliogenesis proteins were observed.
• Ciliary ultrastructure and motility were significantly disrupted in cells and tissues from mutant mice.

Conclusions:

• SRSF1 shuttling is essential for reprogramming gene expression networks during high cellular demands, such as motile ciliogenesis.
• Nuclear retention of SRSF1 disrupts multiciliogenesis and leads to developmental abnormalities.
• These findings highlight the critical role of nucleocytoplasmic shuttling in regulating gene expression for complex cellular processes.