# The unfolded protein response as a mechanism for cellular identity in the developing olfactory system

> **NIH NIH F30** · COLUMBIA UNIVERSITY HEALTH SCIENCES · 2020 · $45,525

## Abstract

PROJECT SUMMARY
In neural development, genetic programs endow each neuron with a distinct cellular identity. This identity
includes a repertoire of molecules on the cell surface that dictate how that neuron will respond to the environment
it encounters as it projects to form neural circuits. A large body of work has focused on how the interactions
between cell surface identity molecules and ligands in the extracellular space guide neural projections, yet it
remains comparatively unclear how mammals generate the stunning diversity of neuronal identities that underly
these intricate networks of connectivity. The mammalian olfactory system offers a perfect microcosm of this
question. Here, developing olfactory sensory neurons (OSN) chose to express a single olfactory receptor (OR)
from roughly 1,500 possibilities in the mouse genome. OR choice sets the components of OSN cellular identity
that direct targeting, endowing an OSN with a “barcode” of cell surface molecules that specifies a precise location
in the olfactory bulb (OB) to which all cells choosing that OR will project. The composition of this barcode is
known and includes neural activity-independent molecules (Neuropilin-1/Semaphorin-3A, Neuropilin-
2/Semaphorin-3F) as well as activity-dependent molecules (Kirrel2-3, Ephrin-A5 and its receptor, non-canonical
Protocadherins). However, the mechanisms mapping OR choice to a specific identity barcode are incompletely
understood. We previously reported that OR choice during OSN development triggers the unfolded protein
response (UPR), a genome-wide mRNA translation-regulatory program essential for complete neuronal
maturation and stable OR expression. Preliminary data suggests that the UPR is differentially active in OSNs
depending on the OR that they chose. Remarkably, these differences are intimately linked to expression patterns
for several neuronal activity-dependent components of the OSN cell surface axon targeting barcode, as well as
three transcription factors with possible roles in organizing the barcode. These results suggest an entirely novel
role for the UPR as a molecular determinant of neuronal identity in the context of axon guidance. We will test
this hypothesis in three specific aims. In aim 1, we will use two mouse genetic approaches to demonstrate
that differential activation of the UPR causally affects OSN cellular identity and axon targeting. Aim 2 will
define the molecular cascade linking the UPR to these identity molecules by identifying master regulator
transcription factors (mrTFs) controlling UPR-mediated cellular identity. Finally, aim 3 will determine
how hierarchical OR-dependent and OR-independent roles for the UPR work together to shape the whole
of OSN identity. We anticipate that these experiments will unveil a previously undescribed role for the UPR as
a molecular determinant of neuronal identity relevant for axon guidance in the olfactory system, offering a new
paradigm with which to study neural development in t...

## Key facts

- **NIH application ID:** 10136320
- **Project number:** 1F30DC019263-01
- **Recipient organization:** COLUMBIA UNIVERSITY HEALTH SCIENCES
- **Principal Investigator:** Hani John Shayya
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $45,525
- **Award type:** 1
- **Project period:** 2020-09-15 → 2024-09-14

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10136320

## Citation

> US National Institutes of Health, RePORTER application 10136320, The unfolded protein response as a mechanism for cellular identity in the developing olfactory system (1F30DC019263-01). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10136320. Licensed CC0.

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