Abstract

ABSTRACTTechnology has led to rapid progress in the identification of genes involved in neurodevelopmental disorders such as intellectual disability (ID), but our functional understanding of the causative genes is lagging. Here, we show that the SWI/SNF chromatin remodelling complex is one of the most over-represented cellular components disrupted in ID. We investigated the role of individual subunits of this large protein complex using targeted RNA interference in post-mitotic memory-forming neurons of the Drosophila mushroom body (MB). Knockdown flies were tested for defects in MB morphology, short-term memory and long-term memory. Using this approach, we identified distinct roles for individual subunits of the Drosophila SWI/SNF complex. Bap60, Snr1 and E(y)3 are required for pruning of the MBγ neurons during pupal morphogenesis, while Brm and Osa are required for survival of MBγ axons during ageing. We used the courtship conditioning assay to test the effect of MB-specific SWI/SNF knockdown on short- and long-term memory. Several subunits, including Brm, Bap60, Snr1 and E(y)3, were required in the MB for both short- and long-term memory. In contrast, Osa knockdown only reduced long-term memory. Our results suggest that individual components of the SWI/SNF complex have different roles in the regulation of structural plasticity, survival and functionality of post-mitotic MB neurons. This study highlights the many possible processes that might be disrupted in SWI/SNF-related ID disorders. Our broad phenotypic characterization provides a starting point for understanding SWI/SNF-mediated gene regulatory mechanisms that are important for development and function of post-mitotic neurons.

Highlights

  • The SWI/SNF complex is the most enriched cellular component among dominant ID genes (DIGs) Considering that most Intellectual disability (ID) cases are caused by dominant de novo mutations, we investigated whether known DIGs possess any common functionality

  • We show that DIGs are highly connected and enriched for functions related to neuronal signalling and chromatin regulation (Fig. 1)

  • In a screen targeting memory-forming neurons of the Drosophila mushroom body (MB), we identified a novel role for several individual components of this complex in post-mitotic neuronal processes, including neuron remodelling, survival and memory formation (Figs 3-6)

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Summary

Introduction

Intellectual disability (ID) is a neurodevelopmental disorder characterized by early-onset limitations in cognitive function and. About two-thirds of known ID genes follow a recessive or X-linked inheritance pattern. Recent studies suggest that recessive and X-linked inheritance patterns are not representative of the majority of ID cases (de Ligt et al, 2012; Gilissen et al, 2014; Rauch et al, 2012; The Deciphering Developmental Disorders Study, 2014; Veltman and Brunner, 2012; Vissers et al, 2010). Several largescale studies on cohorts of patients with variable clinical presentation paint a similar picture, with a prominent role for dominant ID genes (DIGs) (de Ligt et al, 2012; Hamdan et al, 2014; Rauch et al, 2012; The Deciphering Developmental Disorders Study, 2014)

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