# Transfer RNA Dynamics During Neural Differentiation

> **NIH NIH R21** · UNIVERSITY OF CALIFORNIA, MERCED · 2021 · $413,429

## Abstract

Transfer RNA Dynamics During Neural Differentiation
Far from serving as invariant mRNA decoders, transfer RNAs (tRNAs) play a dynamic role in shaping gene
expression. For example, tRNA abundance is expected to affect mRNA stability: transcripts enriched in
optimal codons (decoded by abundant tRNAs) are stable while transcripts enriched in non-optimal codons
(decoded by rare tRNAs) are unstable. We will test this model using differentiation of Drosophila neural stem
cells (neuroblasts) as a highly tractable system with relevance to human neurodevelopment and neurological
disease. We hypothesize that tRNA levels differ between neuroblasts and their neuronal progeny, thereby
influencing mRNA stability and fine-tuning gene expression to meet the needs of each cell type. We also
hypothesize that tRNA gene (tDNA) transcription during neural differentiation is regulated by two non-exclusive
mechanisms: widespread repression of RNA polymerase III (RPOL3) by a neural-specific inhibitor and more
targeted repression of RPOL3 due to overlapping RNA polymerase II (RPOL2)-dependent transcription. We
will test these hypotheses using quantification of tRNA abundance, tRNA transcription and mRNA decay in
neuroblasts and neurons, combined with pharmacologic and genetic manipulation of predicted regulators of
tDNA transcription. We will determine the functional significance of differential tRNA expression using targeted
tRNA knockdown and overexpression in assays of mRNA decay, neurodevelopment and behavior. This work
will be made possible through the development of novel tools for altering tRNA expression, including a
CRISPR / Cas9-based approach. Defective tRNA expression is implicated in several neurodevelopmental and
neurological diseases, including neurodegenerative diseases, multiple forms of microcephaly, and brain
cancers. We will use our expertise in Drosophila neurobiology and RNA biology to significantly advance the
understanding of tRNA expression dynamics that regulate normal development and, when defective, contribute
to disease.

## Key facts

- **NIH application ID:** 10196272
- **Project number:** 1R21NS121995-01
- **Recipient organization:** UNIVERSITY OF CALIFORNIA, MERCED
- **Principal Investigator:** Michael Cleary
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $413,429
- **Award type:** 1
- **Project period:** 2021-04-01 → 2024-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10196272

## Citation

> US National Institutes of Health, RePORTER application 10196272, Transfer RNA Dynamics During Neural Differentiation (1R21NS121995-01). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10196272. Licensed CC0.

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