SRSF10 regulates oligodendrocyte differentiation during mouse central nervous system development by modulating...

Area of Science:

• Neuroscience
• Molecular Biology
• Developmental Biology

Background:

• Oligodendrocyte lineage cells (OLCs) are vital for myelination in the central nervous system (CNS).
• The precise regulation of OLC differentiation and myelination is critical for CNS development and function.
• The role of specific splicing factors, like SRSF10, in these processes remains incompletely understood.

Purpose of the Study:

• To investigate the function of the splicing factor SRSF10 in OLC development and CNS myelination.
• To elucidate the regulatory mechanisms by which SRSF10 influences OLC differentiation.
• To identify SRSF10-regulated genes and alternative splicing events critical for myelination.

Main Methods:

• Conditional depletion of SRSF10 in OLCs in vivo and in vitro.
• Analysis of OLC differentiation, proliferation, apoptosis, and myelination.
• RNA sequencing (RNA-seq) and RNA-immunoprecipitation sequencing (RIP-Seq) to identify SRSF10 targets.
• Antisense oligonucleotide (ASO)-mediated rescue experiments targeting Myo5a alternative splicing.

Main Results:

• Depletion of SRSF10 in OLCs led to hypomyelination and reduced OLC numbers in the developing mouse CNS.
• SRSF10 primarily affects early OLC differentiation stages, without impacting proliferation or apoptosis.
• SRSF10 directly regulates alternative splicing (AS) of numerous genes, including Myo5a.
• Restoring Myo5a AS using ASOs reversed the differentiation defect caused by SRSF10 depletion.

Conclusions:

• SRSF10 is a key regulator of early oligodendrocyte lineage cell differentiation.
• SRSF10 controls myelination by modulating the alternative splicing of critical target genes, such as Myo5a.
• These findings offer insights into OLC development and potential therapeutic targets for dysmyelination disorders.