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

• Published in: eLife Vol. 10
• Main Authors: Hatch, Hayden AM, Belalcazar, Helen M, Marshall, Owen J, Secombe, Julie
• Format: Journal Article
• Language: English
• Published: England eLife Science Publications, Ltd 17-03-2021; eLife Sciences Publications Ltd; eLife Sciences Publications, Ltd
• Subjects: Adults; Analysis; Animal cognition; Animals; Central Nervous System - growth & development; Central Nervous System - metabolism; Chromosomes and Gene Expression; Drosophila; Drosophila - genetics; Drosophila - metabolism; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Gene expression; Gene Expression Regulation, Developmental; Genes; Genetic aspects; Genetic research; Genetic transcription; histone demethylase; Histone Demethylases - genetics; Histone Demethylases - metabolism; Histones; Insects; Intellectual disabilities; intellectual disability; KDM5; Kenyon cell; Larva - growth & development; Larva - metabolism; Lysine; Morphogenesis; Morphology; Mushroom bodies; Mushroom Bodies - metabolism; mushroom body; Mutation; Nerve Tissue Proteins - genetics; Nerve Tissue Proteins - metabolism; Neurodevelopment; Neuromodulation; Neurons; Neurons - metabolism; Neuroscience; Nuclear Proteins - genetics; Nuclear Proteins - metabolism; Proteins; transcription factors; Transcription Factors - genetics; Transcription Factors - metabolism; KDM5; Kenyon cell; transcription factors; neuroscience; chromosomes; mushroom body; D. melanogaster; histone demethylase; gene expression; intellectual disability
• ISSN: 2050-084X; 2050-084X
• DOI: 10.7554/eLife.63886

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
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
, 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.