Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Hani Shayya
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Martín Escamilla del Arenal
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Miao Wang
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Jerome Kahiapo
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Aileen Ugurbil
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Abdurrahman Keskin
Department of Biological Sciences, Columbia University, New York, NY 10027, USA
Fiona Clowney
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Elizaveta V. Bashkirova
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Ariel D. Pourmorady
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Ira Schieren
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Humberto Ibarra Avila
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA
Luke E. Berchowitz
Department of Genetics and Development, Columbia University, Vagelos College of Physicians and Surgeons, New York, NY 10032, USA
Francisco M. Barriga
Systems Oncology Program, Vall d’Hebron Institute of Oncology (VHIO), Vall d’Hebron Barcelona Hospital Campus, 08035 Barcelona, Spain; Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain
Eduard Batlle
Institute for Research in Biomedicine (IRB Barcelona), The Barcelona Institute of Science and Technology (BIST), Baldiri i Reixac 10, 08028 Barcelona, Spain; Centro de Investigación Biomédica en Red de Cáncer (CIBERONC), Barcelona, Spain; Institució Catalana de Recerca i Estudis Avançats (ICREA), Barcelona, Spain
Marko Jovanovic
Department of Biological Sciences, Columbia University, New York, NY 10027, USA
Stavros Lomvardas
Mortimer B. Zuckerman Mind, Brain, and Behavior Institute, Columbia University, New York, NY 10027, USA; Kavli Institute for Brain Sciences at Columbia University, New York, NY 10027, USA; Department of Biochemistry and Molecular Biophysics, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Corresponding author
Summary: Olfactory sensory neurons (OSNs) use olfactory receptor (OR)-specific patterns of endoplasmic reticulum (ER) stress to transform OR sequence identity into axon guidance precision. However, during neuronal differentiation, OSNs transiently co-express random combinations of OR genes, which could generate unpredictable ER stress signatures that could lead to axon miswiring. Here, we show that post-transcriptional OR silencing by the transiently expressed and cytoplasmic RING and KH domain protein Mex3a, decouples OR transcription from OR protein-induced ER stress, until the onset of singular OR transcription. Consequently, conditional Mex3a deletion results in premature ER stress during the polygenic stage of OR transcription, which biases OR choice toward the OR alleles that are transcribed first and perturbs the specificity of OR-regulated axon targeting, disrupting the glomerular map of odor representation in the olfactory bulb. Our experiments reveal the critical role of post-transcriptional gene regulation in a fundamental cellular pathway that influences the assembly of neuronal circuits.
