Lmx1b is required at multiple stages to build expansive serotonergic axon architectures
- Case Western Reserve University, United States
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.
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Lmx1b is required at multiple stages to build expansive serotonergic axon architecturesNCBI Gene Expression Omnibus, GSE130514.
Article and author information
Author details
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
- Anne E West, Duke University School of Medicine, United States
Publication history
- Received: May 24, 2019
- Accepted: July 27, 2019
- Accepted Manuscript published: July 29, 2019 (version 1)
- 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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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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