ER stress transforms random olfactory receptor choice into axon targeting precision

Hani J Shayya; Jerome K Kahiapo; Rachel Duffié; Katherine S Lehmann; Lisa Bashkirova; Kevin Monahan; Ryan P Dalton; Joanna Gao; Song Jiao; Ira Schieren; Leonardo Belluscio; Stavros Lomvardas

doi:10.1016/j.cell.2022.08.025

ER stress transforms random olfactory receptor choice into axon targeting precision

Cell. 2022 Oct 13;185(21):3896-3912.e22. doi: 10.1016/j.cell.2022.08.025. Epub 2022 Sep 26.

Authors

Affiliations

¹ Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA; Medical Scientist Training Program, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
² Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA; Integrated Program in Cellular, Molecular, and Biomedical Studies, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
³ Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA.
⁴ Developmental Neural Plasticity Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892, USA.
⁵ The Miller Institute for Basic Research in Science, University of California, Berkeley, Berkeley, CA 94720, USA.
⁶ Barnard College, New York, NY 10025, USA.
⁷ Mortimer B. Zuckerman Mind, Brain and Behavior Institute, Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Department of Neuroscience, Columbia University Irving Medical Center, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA. Electronic address: sl682@cumc.columbia.edu.

Abstract

Olfactory sensory neurons (OSNs) convert the stochastic choice of one of >1,000 olfactory receptor (OR) genes into precise and stereotyped axon targeting of OR-specific glomeruli in the olfactory bulb. Here, we show that the PERK arm of the unfolded protein response (UPR) regulates both the glomerular coalescence of like axons and the specificity of their projections. Subtle differences in OR protein sequences lead to distinct patterns of endoplasmic reticulum (ER) stress during OSN development, converting OR identity into distinct gene expression signatures. We identify the transcription factor Ddit3 as a key effector of PERK signaling that maps OR-dependent ER stress patterns to the transcriptional regulation of axon guidance and cell-adhesion genes, instructing targeting precision. Our results extend the known functions of the UPR from a quality-control pathway that protects cells from misfolded proteins to a sensor of cellular identity that interprets physiological states to direct axon wiring.

Keywords: Ddit3; PERK; axon guidance; axon targeting; cell adhesion; extracellular barcodes; olfactory receptors; stochastic gene choice; transcriptional networks; unfolded protein response.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Axons / metabolism*
Endoplasmic Reticulum Stress*
Mice
Olfactory Bulb
Olfactory Receptor Neurons / metabolism
Receptors, Odorant* / genetics
Receptors, Odorant* / metabolism
Transcription Factors / metabolism

Substances

Receptors, Odorant
Transcription Factors

Abstract

Publication types

MeSH terms

Substances

Grants and funding