Cortical RORβ is required for layer 4 transcriptional identity and barrel integrity

  1. Erin A Clark  Is a corresponding author
  2. Michael Rutlin
  3. Lucia Capano
  4. Samuel Aviles
  5. Jordan R Saadon
  6. Praveen Taneja
  7. Qiyu Zhang
  8. James B Bullis
  9. Timothy Lauer
  10. Emma Myers
  11. Anton Schulmann
  12. Douglas Forrest
  13. Sacha B Nelson  Is a corresponding author
  1. Brandeis University, United States
  2. Janelia Research Campus, Howard Hughes Medical Institute, United States
  3. National Institutes of Health, NIDDK, United States

Abstract

Retinoic Acid-Related Orphan Receptor Beta (RORβ) is a transcription factor (TF) and marker of layer 4 (L4) neurons, which are distinctive both in transcriptional identity and the ability to form aggregates such as barrels in rodent somatosensory cortex. However, the relationship between transcriptional identity and L4 cytoarchitecture is largely unknown. We find RORβ is required in the cortex for L4 aggregation into barrels and thalamocortical afferent (TCA) segregation. Interestingly, barrel organization also degrades with age in wildtype mice. Loss of RORβ delays excitatory input and disrupts gene expression and chromatin accessibility, with down-regulation of L4 and up-regulation of L5 genes, suggesting a disruption in cellular specification. Expression and binding site accessibility change for many other TFs, including closure of neurodevelopmental TF binding sites and increased expression and binding capacity of activity-regulated TFs. Lastly, a putative target of RORβ, Thsd7a, is down-regulated without RORβ, and Thsd7a knock-out alone disrupts TCA organization in adult barrels.

Data availability

Raw and processed RNA-seq and ATAC-seq files are available at GEO accession GSE138001.

The following data sets were generated

Article and author information

Author details

  1. Erin A Clark

    Department of Biology, Brandeis University, Waltham, United States
    For correspondence
    eaclark@brandeis.edu
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-4013-325X
  2. Michael Rutlin

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  3. Lucia Capano

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3470-9360
  4. Samuel Aviles

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  5. Jordan R Saadon

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  6. Praveen Taneja

    Department of Biology and National Center for Behavioral Genomics, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  7. Qiyu Zhang

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-7141-4046
  8. James B Bullis

    Department of Biology and National Center for Behavioral Genomics, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  9. Timothy Lauer

    Department of Biology, Brandeis University, Brandeis University, United States
    Competing interests
    No competing interests declared.
  10. Emma Myers

    Department of Biology, Brandeis University, Waltham, United States
    Competing interests
    No competing interests declared.
  11. Anton Schulmann

    Janelia Research Campus, Howard Hughes Medical Institute, Ashburn, United States
    Competing interests
    No competing interests declared.
  12. Douglas Forrest

    Laboratory of Endocrinology and Receptor Biology, National Institutes of Health, NIDDK, Bethesda, United States
    Competing interests
    No competing interests declared.
  13. Sacha B Nelson

    Department of Biology, Volen Center for Complex Systems, Brandeis University, Waltham, United States
    For correspondence
    nelson@brandeis.edu
    Competing interests
    Sacha B Nelson, Reviewing editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-0108-8599

Funding

National Institute of Neurological Disorders and Stroke (NS109916)

  • Erin A Clark
  • Michael Rutlin
  • Lucia Capano
  • Samuel Aviles
  • Jordan R Saadon
  • Praveen Taneja
  • Qiyu Zhang
  • James B Bullis
  • Timothy Lauer
  • Emma Myers
  • Anton Schulmann

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All experiments were conducted in accordance with the requirements ofthe Institutional Animal Care and Use Committees at Brandeis University (protocol #17001).

Reviewing Editor

  1. Anne E West, Duke University School of Medicine, United States

Publication history

  1. Received: October 2, 2019
  2. Accepted: August 26, 2020
  3. Accepted Manuscript published: August 27, 2020 (version 1)
  4. Version of Record published: September 15, 2020 (version 2)

Copyright

This is an open-access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

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  1. Erin A Clark
  2. Michael Rutlin
  3. Lucia Capano
  4. Samuel Aviles
  5. Jordan R Saadon
  6. Praveen Taneja
  7. Qiyu Zhang
  8. James B Bullis
  9. Timothy Lauer
  10. Emma Myers
  11. Anton Schulmann
  12. Douglas Forrest
  13. Sacha B Nelson
(2020)
Cortical RORβ is required for layer 4 transcriptional identity and barrel integrity
eLife 9:e52370.
https://doi.org/10.7554/eLife.52370

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