A KDM5-Prospero transcriptional axis functions during early neurodevelopment to regulate mushroom body formation
Abstract
Mutations in the lysine demethylase 5 (KDM5) family of transcriptional regulators are associated with intellectual disability, yet little is known regarding their spatiotemporal requirements or neurodevelopmental contributions. Utilizing the mushroom body (MB), a major learning and memory center within the Drosophila brain, we demonstrate that KDM5 is required within ganglion mother cells and immature neurons for proper axogenesis. Moreover, the mechanism by which KDM5 functions in this context is independent of its canonical histone demethylase activity. Using in vivo transcriptional and binding analyses, we identify a network of genes directly regulated by KDM5 that are critical modulators of neurodevelopment. We find that KDM5 directly regulates the expression of prospero, a transcription factor that we demonstrate is essential for MB morphogenesis. Prospero functions downstream of KDM5 and binds to approximately half of KDM5-regulated genes. Together, our data provide evidence for a KDM5-Prospero transcriptional axis that is essential for proper MB development.
Data availability
TaDa data have been deposited in GEO under the accession codes GSE156101 and GSE166116.
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Genome-wide binding profiles of HP1a and Prospero in Drosophila central brain neural precursors and neuronsNCBI Gene Expression Omnibus, GSE136413.
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RNA-seq analysis of kdm5 null mutant wing discsNCBI Gene Expression Omnibus, GSE109201.
Article and author information
Author details
Funding
National Institutes of Health (R01GM112783)
- Julie Secombe
National Health and Medical Research Council (APP1128784)
- Owen J Marshall
National Health and Medical Research Council (APP1185220)
- Owen J Marshall
National Institutes of Health (F31NS110278)
- Hayden AM Hatch
National Institutes of Health (T32GM007288)
- Hayden AM Hatch
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Laura A Bradfield, University of Technology Sydney, Australia
Publication history
- Received: October 9, 2020
- Accepted: March 16, 2021
- Accepted Manuscript published: March 17, 2021 (version 1)
- Version of Record published: March 26, 2021 (version 2)
Copyright
© 2021, Hatch 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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