Precise temporal regulation of alternative splicing during neural development.

Area of Science:

• Neuroscience
• Molecular Biology
• Genetics

Background:

• Alternative splicing (AS) is a critical gene expression regulatory mechanism during neurodevelopment.
• The precise timing and regulatory networks governing developmental splicing shifts remain largely unknown.

Purpose of the Study:

• To systematically analyze the temporal regulation of AS during mouse cortical development.
• To identify the regulatory mechanisms and RNA-binding proteins controlling developmental splicing switches.
• To investigate the impact of altered splicing programs in specific neuronal subtypes.

Main Methods:

• Analysis of extensive transcriptome profiles from developing mouse cortices, purified neuronal subtypes, and in vitro differentiated neurons.
• Identification and classification of early-switch and late-switch exons.
• Integrative modeling to predict regulatory networks involving RNA-binding proteins (Nova, Rbfox, Mbnl, Ptbp).

Main Results:

• Developmental splicing switches in early-switch and late-switch exons correlate with distinct gene functions and define neuronal maturation stages.
• Neuronal RNA-binding proteins, including Nova, Rbfox, Mbnl, and Ptbp, directly and combinatorially regulate these splicing switches.
• Specific sensory neuronal subtypes lacking Nova and/or Rbfox exhibit an immature splicing program, impacting synaptic gene expression.

Conclusions:

• Splicing switches are precisely timed events that mark neuronal maturation.
• A combinatorial code of RNA-binding proteins governs the neurodevelopmental transcriptome.
• Dysregulation of splicing in specific neuronal subtypes may underlie functional deficits.