DLGS97/SAP97 Is Developmentally Upregulated and Is Required for Complex Adult Behaviors and Synapse Morphology and Function

Abstract

The synaptic membrane-associated guanylate kinase (MAGUK) scaffolding protein family is thought to play key roles in synapse assembly and synaptic plasticity. Evidence supporting these roles in vivo is scarce, as a consequence of gene redundancy in mammals. The genome of Drosophila contains only one MAGUK gene, discs large (dlg), from which two major proteins originate: DLGA [PSD95 (postsynaptic density 95)-like] and DLGS97 [SAP97 (synapse-associated protein)-like]. These differ only by the inclusion in DLGS97 of an L27 domain, important for the formation of supramolecular assemblies. Known dlg mutations affect both forms and are lethal at larval stages attributable to tumoral overgrowth of epithelia. We generated independent null mutations for each, dlgA and dlgS97. These allowed unveiling of a shift in expression during the development of the nervous system: predominant expression of DLGA in the embryo, balanced expression of both during larval stages, and almost exclusive DLGS97 expression in the adult brain. Loss of embryonic DLGS97 does not alter the development of the nervous system. At larval stages, DLGA and DLGS97 fulfill both unique and partially redundant functions in the neuromuscular junction. Contrary to dlg and dlgA mutants, dlgS97 mutants are viable to adulthood, but they exhibit marked alterations in complex behaviors such as phototaxis, circadian activity, and courtship, whereas simpler behaviors like locomotion and odor and light perception are spared. We propose that the increased repertoire of associations of a synaptic scaffold protein given by an additional domain of protein-protein interaction underlies its ability to integrate molecular networks required for complex functions in adult synapses.

Proper splicing contributes to visual function in the aging Drosophila eye

“…However, we also detected alternative transcription start site usage and differential splicing events in both the 5′ and 3′ untranslated regions, which could represent alternative promoter usage and/or polyadenylation. The genes that were differentially spliced with age in the eye were enriched for somewhat broad GO categories including negative regulation of neuron differentiation and cell–cell signaling and include genes that have previously been shown to play a role in visual function in flies including discs large 1 (dlg1) , branchless (bnl), and Na/Ca‐exchange protein ( Calx ; Mendoza‐Topaz et al, 2008; Mukherjee, Choi, & Banerjee, 2012; Wang et al, 2005). The Drosophila compound eye contains a number of cell types in addition to photoreceptors including additional structural and pigment cells (Ready, Hanson, & Benzer, 1976).…”

“…Here, we find that seven of the genes with altered splicing in aging Drosophila photoreceptors have predicted human orthologs associated with human eye disease (Supporting Information Table S5). At least one of the genes with altered splicing in aging photoreceptors provides an intriguing candidate for a link between defective splicing and reduced visual function: dlg1 shows an age‐related change in its splicing profile that would favor expression of a protein product lacking its N‐terminal domain, which is necessary for visual function (Supporting Information Figure S3; Mendoza‐Topaz et al, 2008). Expression of RNAi against Psi also increased the proportion of the transcript that lacks the N‐terminal domain, although these changes were not statistically significant due to high variability in the Psi qPCR data for this gene (Figure 5b).…”

Dynamic changes in host–virus interactions associated with colony founding and social environment in fire ant queens (Solenopsis invicta)

“…2012), disc large 1 ( dlg1 ) regulates complex behaviors including phototaxis and circadian activity (Mendoza‐Topaz et al. 2008), clockwork orange ( cwo ) and Dmel_CG5237 ( unc79 ) also operate in circadian clock neurons to promote rhythmic behavior (Richier et al. 2008; Lear et al.…”

Transmission, Development, and Plasticity of Synapses

“…The dlg locus generates multiple isoforms, but the two major products at the NMJ are DlgA and DlgS97, which differ in the presence of an L27 domain in DLGS97 (Mendoza et al 2003). Both of these isoforms are required to regulate synaptic size (Mendoza-Topaz et al 2008), and DlgS97 specifically interacts with the PDZ domain protein DLin-7 and the MAGUK protein Metro in this process (Bachmann et al 2010). Mutants for fasII similarly results in expanded synaptic size and multiple T-bars (Stewart et al 1996).…”