Alternative splicing-triggered mRNA decay informs splice-switching targets for neurodevelopmental disorders.

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• Alternative splicing-triggered nonsense-mediated mRNA decay (AS-NMD) is a key gene expression regulator.
• The role of AS-NMD in neuronal gene regulation is not well understood.
• Understanding AS-NMD in the brain is crucial for neurodevelopmental disorder research.

Purpose of the Study:

• To investigate the role of AS-NMD in regulating neuronal genes during brain development.
• To identify specific genes and pathways regulated by AS-NMD in the brain.
• To explore AS-NMD as a therapeutic target for neurodevelopmental disorders.

Main Methods:

• Identification and validation of developmentally regulated AS-NMD exons in mouse and human brain tissue and cultured neurons.
• Analysis of AS-NMD regulation in genes associated with neurodevelopmental disorders (NDDs).
• Experimental manipulation of AS-NMD using splice-switching antisense oligonucleotides in the GRIA2 gene.

Main Results:

• Over 3,000 developmentally regulated AS-NMD exons were identified in mammalian brains.
• AS-NMD was found to suppress synaptic genes during brain development.
• Differential regulation of over 200 causal genes for NDDs by AS-NMD was observed.
• An AS-NMD exon in GRIA2 was identified, and its NMD was suppressed using antisense oligonucleotides, increasing functional isoforms.

Conclusions:

• AS-NMD significantly impacts gene expression in the brain, particularly during development.
• AS-NMD plays a role in suppressing synaptic genes and regulating genes linked to NDDs.
• Targeting AS-NMD, exemplified by GRIA2 modulation, offers a potential therapeutic strategy for dominant NDDs like autism spectrum disorders and developmental epileptic encephalopathy.