# The regulation and function of neuron-specific alternative splicing

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA RIVERSIDE · 2020 · $344,613

## Abstract

Given the increasing evidence that RNA binding proteins (RBPs) serve as genetic causes or predisposing risk
factors underlying a wide spectrum of neurological diseases, a pressing need exists to understand their
specific cellular functions in developing and mature brains. Similar to transcription factors, RBPs could be
master regulators of certain cellular processes owing to their coordinated target sets. Unlike widely-studied
transcription factors, the physiological functions of RBPs are historically underexplored. Most of the dozen
RBPs found to exhibit tissue-specific expression are involved in regulating neuronal alternative splicing. We
and others have revealed the large-scale genetic programming of alternative splicing during embryonic brain
development, resulting in neuron-specific alternative isoforms in mature brains. We show many of these
splicing changes are mediated by a nuclear RBP, polypyrimidine tract-binding protein 2 (PTBP2). PTBP2
exhibits dynamic temporal expression during neuronal differentiation and may orchestrate the developmental
programming of alternative splicing in order to accomplish the prolonged and continuous neuronal
morphological transformations. Our previous study shows that downregulation of PTBP2 prior to
synaptogenesis is necessary for spine formation. Our newest data show that PTBP2 has additional functions in
early differentiating neurons prior to synapse formation. Guided by strong preliminary data, we hypothesize
that PTBP2 governs neuron-specific splicing to control the initiation of neuronal polarity. This proposal will
address multiple critical barriers to the study of neuronal polarity and provide a new framework for functional
analysis of alternative splicing. Our long history of researching alternative splicing and PTBP2 in the brain
places us in a unique position to advance these fields. Our team, with complementary expertise in genetics,
neurobiology, and molecular cellular biochemical and computational biology, has demonstrated successful
collaborations. We have generated new tools and resource to thoroughly determine the cellular and molecular
defects caused by Ptbp2 knockout in cortical neurons. Completion of this project will allow us to further our
long-term goal of revealing new genetic, molecular and cellular controls of neuronal polarity and
morphogenesis that enables neural circuit formation.

## Key facts

- **NIH application ID:** 9842633
- **Project number:** 5R01NS104041-03
- **Recipient organization:** UNIVERSITY OF CALIFORNIA RIVERSIDE
- **Principal Investigator:** Sika Zheng
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $344,613
- **Award type:** 5
- **Project period:** 2017-12-15 → 2022-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9842633

## Citation

> US National Institutes of Health, RePORTER application 9842633, The regulation and function of neuron-specific alternative splicing (5R01NS104041-03). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9842633. Licensed CC0.

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