The chromatin remodeler ISWI acts during Drosophila development to regulate adult sleep

Abstract

Sleep disruptions are among the most commonly reported symptoms across neurodevelopmental disorders (NDDs), but mechanisms linking brain development to normal sleep are largely unknown. From a Drosophila screen of human NDD-associated risk genes, we identified the chromatin remodeler Imitation SWItch/SNF (ISWI) to be required for adult fly sleep. Loss of ISWI also results in disrupted circadian rhythms, memory, and social behavior, but ISWI acts in different cells and during distinct developmental times to affect each of these adult behaviors. Specifically, ISWI expression in type I neuroblasts is required for both adult sleep and formation of a learning-associated brain region. Expression in flies of the human ISWI homologs SMARCA1 and SMARCA5 differentially rescues adult phenotypes, while de novo SMARCA5 patient variants fail to rescue sleep. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs and point toward chromatin remodeling machinery as critical for sleep circuit formation.

insomniac links the development and function of a sleep-regulatory circuit

“…Our studies and recent findings ( Gong et al, 2021 ) suggest that proper regulation of neurogenesis is essential for normal sleep and that altered neurogenesis in discrete circuits can cause lifelong sleep dysfunction. Intriguing but fragmentary evidence suggests that other genes whose mutation impacts sleep might similarly alter neurogenesis.…”

“…Here, we have used temporally restricted genetic manipulations to show that inc acts during neuronal development to ultimately impact sleep in adulthood. While many genes are known to act in adults to impact sleep, developmental mechanisms underlying sleep regulation have only recently gained attention ( Chakravarti Dilley et al, 2020 ; Gong et al, 2021 ; Iwasaki et al, 2021 ; Xie et al, 2019 ). Our results underscore the importance of unbiased temporal genetic manipulations to define critical periods through which genes impact sleep, and suggest that genes may influence sleep through unappreciated developmental mechanisms.…”

Pathogenic variants in SMARCA5 , a chromatin remodeler, cause a range of syndromic neurodevelopmental features

“…4, C to E ). Consistent with these findings, Gong et al ( 47 ) reported that Iswi knockdown in flies results in mushroom body morphologic abnormalities, as well as disrupted sleep, circadian rhythmicity, memory, and social behaviors, suggesting that Iswi is required during development for numerous adult behaviors.…”

“…Apart from its previously reported function in cell proliferation/stem cell self-renewal ( 59 ) and hence smaller head/microcephaly, we identified its requirement in postmitotic neurons. Specifically, we found that Iswi LoF leads to defects in sensory neuron dendrite tiling and mushroom body development, highlighting its underappreciated role in neural circuit assembly ( 47 ). This likely contributes to the behavioral deficits such as impaired locomotion in the Iswi knockdown flies and intellectual disability, hypotonia, and speech delay in patients.…”

“…Ppk-CD4tdGFP , ppk-Gal4 , UAS-Iswi RNAi , elav-Gal4 , UAS-mCD8::GFP , and P { CaryP } attP2 have been previously described ( 47 , 60 ). To generate the UAS- SMARCA5 WT , UAS-SMARCA5R 592Q , and UAS-SMARCA5 268-319del stocks, the coding sequences were cloned into a pACU2 vector, and the constructs were then injected (Rainbow Transgenic Flies Inc).…”