The splicing regulator Rbfox2 is required for both cerebellar development and mature motor function

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Rbfox proteins (Rbfox1, Rbfox2, Rbfox3) regulate alternative splicing in neurons.
• Their roles in brain development and function are unclear due to functional redundancy.

Purpose of the Study:

• To investigate the specific roles of Rbfox2 in central nervous system (CNS) development and mature neuronal function.
• To elucidate the molecular mechanisms underlying Rbfox2's function in the brain.

Main Methods:

• Central nervous system-specific deletion of Rbfox2 in mice.
• Genome-wide RNA sequencing (RNA-seq) analysis of Rbfox2 mutant brains.
• Conditional deletion of Rbfox1 and Rbfox2 in mature Purkinje cells.

Main Results:

• CNS-specific Rbfox2 deletion disrupts cerebellar development.
• Rbfox2 deficiency alters splicing of transcripts crucial for brain development and function.
• Deletion of Rbfox1 and Rbfox2 in Purkinje cells causes irregular neuronal firing.
• Improper splicing of Scn8a mRNA (encoding Na(v)1.6 sodium channel) leads to reduced protein expression.

Conclusions:

• Rbfox2 controls a post-transcriptional program essential for proper brain development.
• Rbfox2, along with Rbfox1, maintains mature neuronal physiology, particularly Purkinje cell pacemaking.
• Shared control of sodium channel transcript splicing by Rbfox proteins is vital for neuronal function.