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.
Highlights
Intellectual disability (ID) is reported to affect 1.5–3% of the global population and represents a class of neurodevelopmental disorders characterized by cognitive impairments that result in lifelong educational, social, and financial consequences for patients and their caregivers (van Bokhoven, 2011; Leonard and Wen, 2002)
To assess the neurodevelopmental consequences resulting from KDM5 loss, we examined mushroom body (MB) morphology of animals that were homozygous for a kdm5 null allele, kdm5140 (Drelon et al, 2018; Drelon et al, 2019)
As homozygous kdm5140 animals fail to eclose from their pupal cases, we performed our immunohistochemical analyses on pharate adults, which externally appear indistinguishable from wild-type animals (Drelon et al, 2018)
Summary
Intellectual disability (ID) is reported to affect 1.5–3% of the global population and represents a class of neurodevelopmental disorders characterized by cognitive impairments that result in lifelong educational, social, and financial consequences for patients and their caregivers (van Bokhoven, 2011; Leonard and Wen, 2002). Kdm5c knockout mice display behavioral deficits that are analogous to those exhibited by patients with pathogenic KDM5C variants, such as increased aggression, learning and memory impairments, and decreased seizure thresholds (Iwase et al, 2016; Scandaglia et al, 2017) Together, these studies suggest that the neuromorphological and functional impairments resulting from loss of orthologous KDM5 proteins are likely to be attributed to altered gene expression within neurons. A subset of ID-associated KDM5C missense mutations have been shown in vitro not to affect H3K4me demethylase activity, yet alter transcriptional outputs (Brookes et al, 2015; Vallianatos et al, 2018) These data provide strong evidence that disruption of KDM5 protein function may impact multiple transcriptional pathways critical to neuronal development and function. Our studies provide the first in vivo analysis of KDM5 within a specific cell population, revealing a key kdm5-pros genetic pathway critical for neurodevelopment
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