Lmx1b is required at multiple stages to build expansive serotonergic axon architectures

Abstract

Formation of long-range axons occurs over multiple stages of morphological maturation. However, the intrinsic transcriptional mechanisms that temporally control different stages of axon projection development are unknown. Here, we addressed this question by studying the formation of mouse serotonin (5-HT) axons, the exemplar of long-range profusely arborized axon architectures. We report that LIM homeodomain factor 1b (Lmx1b)-deficient 5-HT neurons fail to generate axonal projections to the forebrain and spinal cord. Stage-specific targeting demonstrates that Lmx1b is required at successive stages to control 5-HT axon primary outgrowth, selective routing, and terminal arborization. We show a Lmx1b→Pet1 regulatory cascade is temporally required for 5-HT arborization and upregulation of the 5-HT axon arborization gene, Protocadherin-alphac2, during postnatal development of forebrain 5-HT axons. Our findings identify a temporal regulatory mechanism in which a single continuously expressed transcription factor functions at successive stages to orchestrate the progressive development of long-range axon architectures enabling expansive neuromodulation.

Data availability

Raw ChIP-seq data GEO accession: GSE74315. RNA-seq data generated in this study and ChIP-seq analysis are deposited in NCBI GEO under accession code GSE130514.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Lauren J Donovan

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  2. William C Spencer

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9700-8011
  3. Meagan M Kitt

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  4. Brent A Eastman

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  5. Katherine J Lobur

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  6. Kexin Jiao

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  7. Jerry Silver

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    Competing interests
    The authors declare that no competing interests exist.
  8. Evan S Deneris

    Department of Neurosciences, Case Western Reserve University, Cleveland, United States
    For correspondence
    esd@case.edu
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-4211-9934

Funding

National Institute of Mental Health (P50 MH096972)

  • Evan S Deneris

National Institute of Mental Health (RO1 MH062723)

  • Evan S Deneris

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

Ethics

Animal experimentation: Animal experimentation: All animal procedures used in this study were in strict accordance with the Guide for the Care and Use of Laboratory Animals of the National Institutes of Health. The protocol was approved by the Case Western Reserve University School of Medicine Institutional Animal Care and Use Committee (Animal Welfare Assurance Number A3145-01, protocol #: 2014-0044).

Reviewing Editor

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

Publication history

  1. Received: May 24, 2019
  2. Accepted: July 27, 2019
  3. Accepted Manuscript published: July 29, 2019 (version 1)
  4. Version of Record published: August 7, 2019 (version 2)

Copyright

© 2019, Donovan et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Lauren J Donovan
  2. William C Spencer
  3. Meagan M Kitt
  4. Brent A Eastman
  5. Katherine J Lobur
  6. Kexin Jiao
  7. Jerry Silver
  8. Evan S Deneris
(2019)
Lmx1b is required at multiple stages to build expansive serotonergic axon architectures
eLife 8:e48788.
https://doi.org/10.7554/eLife.48788

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