# Converting stochastic olfactory receptor expression to stereotypic axon guidance programs

> **NIH NIH R01** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2024 · $530,688

## Abstract

Summary
The mammalian olfactory system has the remarkable ability to detect and identify an astronomical number of
volatile chemicals, termed odorants. Odorants are detected by olfactory receptors (ORs) at the cilia of olfactory
sensory neurons (OSNs), which transform chemical information into electrical signals transmitted to the olfactory
bulb (OB). Each one of the ~1000 OR genes is expressed in a monogenic, monoallelic, and seemingly stochastic
fashion in the main olfactory epithelium (MOE), yet axons from OSNs with the same OR converge to distinct and
stereotypic neuropil structures at the OB called glomeruli. Because each OR identity is represented by
corresponding glomeruli, odor binding to distinct OR repertoires activates an odor-specific combination of
glomeruli, providing the basis of odor perception. Here, we investigate molecular mechanisms that transform the
random expression of a single OR in the MOE to stereotypic and highly coordinated axon targeting programs in
the OB. Previous work revealed that the OR sequence plays an essential regulatory function in this axon
guidance process, in part, by directing the expression programs of genes involved in axon guidance and cell
adhesion. We reveal that the OR identity may inform this process by eliciting distinct levels of endoplasmic
reticulum (ER) stress, which in turn, influence transcriptional programs controlling axon targeting specificity. With
the generation of a translational fluorescent reporter that quantifies the levels of ER stress-induced Perk
signaling, we demonstrate that OSNs have distinct levels of ER stress according to the identity of the OR they
express. Furthermore, by deconvoluting transcriptional networks, we identified transcription factors that
transform ER stress levels into distinct axon guidance outputs. Based on these preliminary findings, we propose
experiments that will decipher the function of ER stress-responsive transcription factors and will identify
extracellular barcodes corresponding to various levels of ER stress. Moreover, we propose experiments that will
untangle the contribution of OR identity and OSN origin to the cellular levels of ER stress and will identify OR
protein sequences with a major role in this process. Our experiments promise to provide novel insight into a
fascinating problem that has remained poorly understood for decades. Moreover, this work will uncover
generalizable mechanisms responsible for converting cellular and molecular identity of neurons into precise axon
guidance specificity, with immense basic and translational ramifications.

## Key facts

- **NIH application ID:** 10744181
- **Project number:** 5R01DC015451-08
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Stavros Lomvardas
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $530,688
- **Award type:** 5
- **Project period:** 2016-07-01 → 2026-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10744181

## Citation

> US National Institutes of Health, RePORTER application 10744181, Converting stochastic olfactory receptor expression to stereotypic axon guidance programs (5R01DC015451-08). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10744181. Licensed CC0.

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