# Co-transcriptional mechanisms of neuronal microexon splicing: causes and consequences for 3' end processing

> **NIH NIH F31** · YALE UNIVERSITY · 2024 · $25,709

## Abstract

PROPOSAL SUMMARY/ABSTRACT
Alternative splicing of pre-mRNA plays a key role in the regulation of gene expression and contributes to protein
diversity between tissue types. Recent work has demonstrated that tissue-specific “microexons” that are 3-27
nucleotides in length are highly conserved in metazoans, play a prominent role in neuronal development, and
are frequently mis-spliced in patients with autism spectrum disorder. Work from the last decade has
demonstrated that splicing frequently occurs during transcription elongation (co-transcriptionally), with introns
rapidly excised following their synthesis. It is unclear how microexons can be defined rapidly enough to be spliced
during transcription elongation when both the 3' and 5' splice sites emerge from the RNA Polymerase II (Pol II)
exit channel nearly simultaneously. Additionally, the co-dependence of microexon splicing with downstream
mRNA processing events is unknown. The work outlined in this proposal, broken down into three independent
aims, will fill substantial gaps in our understanding of neuronal microexon splicing regulation. In Aim 1, I will
adapt sequencing-based methods pioneered in the Neugebauer lab to investigate the relationship between
microexon splicing and transcription elongation. I hypothesize that microexons are spliced under different
transcriptional parameters than “conventional” exons which are on average ten times longer. In Aim 2, I will
analyze single molecules of mRNA to determine processing steps that co-occur in mRNAs with microexons. I
anticipate that microexons will serve to influence downstream processing events (e.g polyA cleavage site
choice). Finally, in Aim 3, I will use a series of splicing reporters to investigate the influence of local mRNA
sequence to microexon splicing. This proposal addresses many unresolved questions related to neuronal
microexon regulation.

## Key facts

- **NIH application ID:** 10908487
- **Project number:** 5F31NS129248-03
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Jackson Gordon
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $25,709
- **Award type:** 5
- **Project period:** 2022-09-01 → 2025-05-20

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10908487

## Citation

> US National Institutes of Health, RePORTER application 10908487, Co-transcriptional mechanisms of neuronal microexon splicing: causes and consequences for 3' end processing (5F31NS129248-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10908487. Licensed CC0.

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