The chromatin remodeler ISWI acts duringDrosophiladevelopment 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 rescue adult phenotypes. We propose that sleep deficits are a primary phenotype of early developmental origin in NDDs, and point towards chromatin remodeling machinery as critical for sleep circuit formation.

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.…”

Pathogenic variants inSMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features

“…Apart from its previously reported function in cell proliferation/stem cell self-renewal ( 57 ) and hence smaller head/microcephaly, we identified its requirement in post-mitotic 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 ( 46 ). 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.…”

“…Consistent with these findings, Gong et al . 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 ( 46 ).…”

“…Ppk-CD4tdGFP, ppk-Gal4, UAS-Iswi RNAi, elav-Gal4, UAS-mCD8::GFP and P { CaryP } attP2 have been previously described ( 46, 58 ). 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).…”