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

Abstract
Data availability
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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

1. Donovan LJ
2. Spencer WC
3. Kitt MM
4. Eastman BA
5. Lobur KJ
6. Jiao K
7. Silver J
8. Deneris ES
(2019) Lmx1b is required at multiple stages to build expansive serotonergic axon architectures
NCBI Gene Expression Omnibus, GSE130514.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE130514

The following previously published data sets were used

1. Wyler SC
2. Spencer WC
3. Green NH
4. Rood BD
5. Crawford L
6. Craige C
7. Gresch P
8. McMahon DG
9. Beck SG
10. Deneris ES
(2016) Pet-1 Switches Transcriptional Targets Postnatally to Regulate Maturation of Serotonin Neuron Excitability.
NCBI Gene Expression Omnibus, GSE74315.

http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE74315

Article and author information

Author details

Lauren J Donovan

Department of Neurosciences, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
William C Spencer

Department of Neurosciences, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-9700-8011
Meagan M Kitt

Department of Neurosciences, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Brent A Eastman

Department of Neurosciences, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Katherine J Lobur

Department of Neurosciences, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Kexin Jiao

Department of Neurosciences, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
Jerry Silver

Department of Neurosciences, Case Western Reserve University, Cleveland, United States

Competing interests
The authors declare that no competing interests exist.
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.

"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).

Copyright

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.