Sensory neuron transcriptomes reveal complex neuron-specific function and regulation of mec-2/Stomatin splicing

Area of Science:

• Molecular Biology
• Neuroscience
• Genetics

Background:

• Cellular function is governed by transcription and RNA binding proteins.
• Single-cell post-transcriptional data analysis faces limitations due to sparsity.
• The Caenorhabditis elegans lineage provides a model for deep transcriptome analysis.

Purpose of the Study:

• To analyze splicing networks by overcoming single-cell data limitations.
• To investigate the role of MEC-8/RBPMS in mechanosensory touch-neuron splicing.
• To understand how MEC-8 regulates cell-specific isoforms.

Main Methods:

• Leveraging the invariant Caenorhabditis elegans cell lineage for deep transcriptomes.
• Performing splicing network analysis with increased sequencing depth and uniformity.
• Utilizing forced endogenous isoform-specific expression to determine function.

Main Results:

• Identified a small MEC-8-regulated network controlling touch-neuron specific isoforms.
• MEC-8 establishes the long mec-2/Stomatin isoform in touch neurons; short isoform predominates elsewhere.
• The short mec-2 isoform is crucial for olfaction, while the long isoform functions in both olfaction and mechanosensation.
• Restoring the long isoform rescues mec-8 mutant mechanosensation, highlighting its critical role.
• A cassette exon within mec-2 generates long/extra-long isoforms, both required for mechanosensation, likely as heteromers.

Conclusions:

• MEC-8 plays a critical role in establishing cell-specific splicing patterns, particularly for mec-2.
• Distinct mec-2 isoforms have specialized functions in different sensory neurons.
• The long mec-2 isoform and its variants are essential for mechanosensation in touch neurons.