A KDM5-Prospero transcriptional axis functions during early neurodevelopment to regulate mushroom body formation

Abstract
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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.

The following previously published data sets were used

1. Liu X
2. Shen J
3. Xie L
4. Wei Z
5. Wong C
6. Li Y
7. Zheng X
8. Li P
9. Song Y
(2020) Genome-wide binding profiles of HP1a and Prospero in Drosophila central brain neural precursors and neurons
NCBI Gene Expression Omnibus, GSE136413.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE136413
(2018) RNA-seq analysis of kdm5 null mutant wing discs
NCBI Gene Expression Omnibus, GSE109201.

https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE109201

Article and author information

Author details

Hayden AM Hatch

Neuroscience, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Helen M Belalcazar

Genetics, Albert Einstein College of Medicine, New York, United States

Competing interests
The authors declare that no competing interests exist.
Owen J Marshall

Menzies Institute for Medical Research, University of Tasmania, Hobart, Australia

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

Genetics and Neuroscience, Albert Einstein College of Medicine, New York, United States

For correspondence
julie.secombe@einsteinmed.org

Competing interests
The authors declare that no competing interests exist.

"This ORCID iD identifies the author of this article:" 0000-0002-5826-7547

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.

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.