# Mechanism of mRNA Localization and Localized Translation in Neurons

> **NIH NIH R01** · ALBERT EINSTEIN COLLEGE OF MEDICINE · 2022 · $665,821

## Abstract

ABSTRACT
The neuron is the basic cellular unit of the brain. For neurons to work properly, they must be plastic and
constantly capable of changing in response to stimuli, forming and stabilizing new connections. This
process requires proteins to be added to the new synaptic contact, and this in turn results from the targeting
of mRNA to these sites of activity, as we have shown in our previous work. This is the molecular basis of
learning and memory since the synapse is stabilized by the production of proteins in response to
stimulation that is important for its function and structural integrity. How this mRNA is regulated in
neurons to make the right protein at the right place and time has been the subject of our investigations
over the years of this funding. This proposal exploits the tools we developed during the last funding period
to address how mRNA is regulated in dendrites. We have expended considerable effort in the generation
of genetically engineered mice wherein the loci of three neuronally expressed genes important for learning
and memory have been tagged with stem loops that, when expressed in the mRNA bind to fluorescent
proteins. The single mRNAs expressed from these genes can be imaged in living cells and extended into
live tissues. We have taken care to verify that the tagging is neutral: it does not alter the behavior or affect
memory formation in the mice. One of these tags is for Arc, an immediate early gene in response to
neuronal stimulation important for consolidating long term memory. Unlike the constitutive -actin
mRNA, which we showed sits at the place where it was last stimulated for hours, Arc mRNA localizes
only for a few minutes, and degrades soon after. The current proposal reports on the progress to solving
how transiently localized mRNAs can impact long term changes at the stimulated spines. The surprise
was that Arc undergoes cycles of localization and translation in response to a single stimulus. Even more
incredible is that the translation occurs spatially at the same spot, so the mRNA in the next cycle finds the
site of previous localization and builds up a continuous “hotspot” of localized protein synthesis. This in
contrast to the β-actin mRNA, which persists at the stimulated site, awaiting the next signal, wherein it
will initiate another round of proteins. Because β-actin is a structural protein, the synaptic contact is built
up with rounds of translation, consistent with a learning and memory paradigm that relies on repetitive
stimulation. The current proposal is directed towards understanding the kinetics of translation hotspots,
and their spatial overlap for different mRNAs with distinct roles in plasticity. We crossed the β-actin and
Arc mice to homozygosity where both mRNAs were individually detectable by different colored
fluorochromes in the same neuron. We have learned from this mouse that the two mRNAs were handled
differently by the neuron, and traveled in independent “granules”, likely result...

## Key facts

- **NIH application ID:** 10586910
- **Project number:** 2R01NS083085-30
- **Recipient organization:** ALBERT EINSTEIN COLLEGE OF MEDICINE
- **Principal Investigator:** Sulagna Das
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $665,821
- **Award type:** 2
- **Project period:** 1992-03-03 → 2027-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586910

## Citation

> US National Institutes of Health, RePORTER application 10586910, Mechanism of mRNA Localization and Localized Translation in Neurons (2R01NS083085-30). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10586910. Licensed CC0.

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