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A spatial code governs olfactory receptor choice and aligns sensory maps in the nose and brain
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A spatial code governs olfactory receptor choice and aligns sensory maps in the nose and brain

David H. Brann, Tatsuya Tsukahara, Cyrus Tau +9 more
May 2025
 ·
bioRxiv
 ·
DOI 
10.1101/2025.05.02.651738
94
%
Reproducible
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It ranks in the top 1% of preprints assessed in Neuroscience this quarter.
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Why this is interesting

Overturning the canonical zonal model, this study shows that a retinoic acid gradient simultaneously encodes receptor identity and axon targeting across all ~1100 olfactory receptors, unifying peripheral sensory organization with central circuit assembly under a single transcriptional code.

Author perspective

What is the most important insight, discovery, or finding from your paper that you would like other scientists to know?
“

Odors are detected through a vast array of odor receptors, but whether these receptors are spatially organized in the nose has remained unclear. Here we show that each of the ~1000 odor receptors in the mouse adopts a unique and stereotypical mean position within the olfactory epithelium; we further unveil a transcriptional program that both builds this precise map, and coordinates connections between sensory neurons in the nose and second order neurons in the brain.

”
Sandeep R. Datta

QED claims analysis

Summary

Olfactory sensory neurons are organized into a precise spatial map of ~1100 distinguishable receptor peaks along the epithelium's dorsoventral axis, created by retinoic acid gradients that coordinate a ~250-gene transcriptional program controlling spatial identity, heterochromatin-mediated OR choice in fate-restricted precursors, and axon guidance to align epithelial receptor positions with stereotyped glomerular maps in the olfactory bulb.

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Main Claim 1 –

Unique DV scores define OSN subtypes via ~250-gene programs

Supporting evidence

  • DV spatial identity arises in precursors before OR choice
  • DV scores encode spatial position, not activity or OR identity
  • Ectopic OR expression shows DV identity is cell-intrinsic
Main Claim 2 –

Each OR subtype forms a distinct DV-peaked epithelial distribution

Supporting evidence

  • Cis-regulatory genomic context, not OR protein, sets OR position
Main Claim 3 –

Spatial position fate-restricts stem cells, biasing stochastic OR choice

Supporting evidence

  • Graded heterochromatin represses mismatched ORs by DV identity
Main Claim 4 –

Retinoic acid gradients rheostatically control DV genes and OR choice

Supporting evidence

  • OR co-expression and choice progress from dorsal to ventral over time

Abstract

Although topographical maps organize many peripheral sensory systems, it remains unclear whether olfactory sensory neurons (OSNs) choose which of the ∼1100 odor receptors (ORs) to express based upon their spatial location in the olfactory epithelium (OE) or instead ORs are scattered randomly. Here we reveal that each OR is expressed at a precise mean position along the OE dorsoventral axis, thereby instantiating a receptor map. This patterning reflects the differential use, by precursors and mature OSNs, of a coherent gene expression program controlled by a spatially-varying retinoic acid gradient; this program — which includes key transcription factors and axon guidance genes — translates position into a spatially appropriate distribution of OR choices and aligns the epithelial map of OR identity with the glomerular map present in the olfactory bulb. These results identify a transcriptional code that distinguishes and spatially organizes the vast array of sensory channels that comprise the olfactory system.

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