Essential roles for the splicing regulator nSR100/SRRM4 during nervous system development

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alternative splicing (AS) creates significant transcriptomic complexity in the vertebrate nervous system.
• The roles of splicing regulators and their networks in nervous system development are not fully understood.

Purpose of the Study:

• To investigate the function of the neural-specific splicing regulator nSR100 (SRRM4) in vertebrate nervous system development.
• To identify the AS regulatory networks controlled by nSR100 and their impact on neurodevelopment.

Main Methods:

• Generation of mice lacking the nSR100/SRRM4 gene.
• Analysis of nervous system development, including neurite outgrowth, cortical layering, and axon guidance.
• Genome-wide assessment of alternative splicing patterns, focusing on microexons.

Main Results:

• Loss of nSR100 leads to impaired central and peripheral nervous system development.
• Widespread changes in AS were observed, with a shift towards non-neural splicing patterns.
• nSR100 regulates a program of neural microexons, including a 6-nt microexon in Unc13b, critical for neuritogenesis.

Conclusions:

• nSR100 plays a critical in vivo role in neurodevelopment.
• nSR100's function is linked to a conserved program of neuronal microexon splicing.
• Dysregulation of nSR100-mediated microexon splicing may contribute to neurological disorders.