# MicroRNA-Dependent Regulation of Synaptic Form, Function and Plasticity at the Neuromuscular Junction

> **NIH NIH P01** · HARVARD MEDICAL SCHOOL · 2020 · $206,486

## Abstract

Project 1 Project Leader: Van Vactor, David L.
Abstract
It has become increasingly clear that neuronal connectivity, function and plasticity all rely on the post-
transcriptional regulation of gene networks. Among newly discovered classes of regulatory factor likely to be
vital for regulating mRNA stability and translation in neurons, small non-coding microRNAs (miRs) have
tremendous potential to shape the gene expression landscape. This large class of sequence-specific
regulatory molecules is highly expressed in the nervous system. However, very few miR functions have been
examined in vivo where the relationship between neural circuit architecture and behavioral outputs are
maintained. To address this challenge, we have recently created tools to manipulate miR function with spatial
and temporal specificity, in a model organism ideal for the study of neural circuits that control a wide variety of
behaviors. Drosophila offers an increasingly sophisticated set of genetic approaches and reagents that are
complementary and enabling to the new tools we have produced. As part of a carefully orchestrated set of
collaborations using multiple robust and fundamental behaviors in this organism, we set out to map the miRs
essential in the neural circuits controlling locomotion, sleep and associative memory. Using the larval NMJ as a
model synapse for genetic validation ideal for miRs that may act in multiple neural circuits or multiple stages of
postembryonic development, we have shown that null mutations recapitulate 85% of our miR-SP bouton
phenotypes tested to date. Our functional screens reveal four conserved miRs likely to shape the development
and plasticity of neural circuits: the miR-13 and miR-92 families, miR-190 and let-7. With an array of
techniques, many of which we are developing with and/or learning from our collaborators, we will determine
which of these miRs are essential for neurotransmission and activity-induced remodeling at the synapse. We
will use new genetic tools to define the spatial and temporal logic for each miR function. We will then use a
state-of-the-art combination of transcriptome sequencing and computational informatics, followed by use of in
vivo activity sensors and functional validation, to discover the downstream mechanisms for each miR that
intersects our coordinated screens. With an initial focus on the miR-92 family, we have obtained preliminary
informatics and expression data identifying several highly conserved target gene candidates that have been
implicated in developmental and activity-dependent synaptic signaling pathways. Once we dissect the cellular
and molecular mechanisms for each gene, we will then compare each miR-target relationship across our
model circuits to determine which mechanisms are context-specific, and which are widely used across the
brain. This combination of comprehensive discovery science and comparative molecular anatomy will address
fundamental and timely questions in a way that is not ye...

## Key facts

- **NIH application ID:** 9910460
- **Project number:** 5P01NS090994-05
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** David L. Van Vactor
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $206,486
- **Award type:** 5
- **Project period:** — → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9910460

## Citation

> US National Institutes of Health, RePORTER application 9910460, MicroRNA-Dependent Regulation of Synaptic Form, Function and Plasticity at the Neuromuscular Junction (5P01NS090994-05). Retrieved via AI Analytics 2026-06-14 from https://api.ai-analytics.org/grant/nih/9910460. Licensed CC0.

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