A role for the membrane protein M6 in the Drosophila visual system

Abstract

BackgroundMembers of the proteolipid protein family, including the four-transmembrane glycoprotein M6a, are involved in neuronal plasticity in mammals. Results from our group previously demonstrated that M6, the only proteolipid protein expressed in Drosophila, localizes to the cell membrane in follicle cells. M6 loss triggers female sterility, which suggests a role for M6 in follicular cell remodeling. These results were the basis of the present study, which focused on the function and requirements of M6 in the fly nervous system.ResultsThe present study identified two novel, tissue-regulated M6 isoforms with variable N- and C- termini, and showed that M6 is the functional fly ortholog of Gpm6a. In the adult brain, the protein was localized to several neuropils, such as the optic lobe, the central complex, and the mushroom bodies. Interestingly, although reduced M6 levels triggered a mild rough-eye phenotype, hypomorphic M6 mutants exhibited a defective response to light.ConclusionsBased on its ability to induce filopodium formation we propose that M6 is key in cell remodeling processes underlying visual system function. These results bring further insight into the role of M6/M6a in biological processes involving neuronal plasticity and behavior in flies and mammals.

Filopodia formation driven by membrane glycoprotein M6a depends on the interaction of its transmembrane domains

“…5a). Gpm6a mutant mice and flies grow normally and lack evident behavioral affections, but mutant mice under mild stress develop claustrophobia (Zappia et al 2012;El-Kordi et al 2013). These results allow us to speculate that mental disorders associated with genetic variants in GPM6A might be linked to a gain-of-function (e.g., retention in the ER or duplications) rather than with an abolishment of gene expression.…”

“…Gpm6a mutant mice and flies grow normally and lack evident behavioral affections, but mutant mice under mild stress develop claustrophobia (Zappia et al . ; El‐Kordi et al . ).…”

“…; Zappia et al . ). M6a positively contributes to neuritogenesis, filopodia outgrowth and synapse formation in M6a‐over‐expressing neurons, but its mechanism of action remains unknown (Alfonso et al .…”

“…M6a is a membrane glycoprotein encoded by the gene GPM6A. M6a, together with M6b, proteolipid protein (PLP) and DM20, belongs to the PLP family, and has been related to neuronal plasticity in different experimental models (Lagenaur et al 1992;Alfonso et al 2005;Michibata et al 2009;Huang et al 2011;Sato et al 2011a;Zappia et al 2012). M6a positively contributes to neuritogenesis, filopodia outgrowth and synapse formation in M6a-over-expressing neurons, but its mechanism of action remains unknown (Alfonso et al 2005;Fuchsova et al 2009;Formoso et al 2015).…”

Altered expression of neuroplasticity-related genes in the brain of depressed suicides

“…For example, GPM6A potential involvement in the hippocampus-dependent memory would be in agreement with the impaired long-term memory performance of M6 (GPM6A ortholog in fly)-deficient and overexpressing flies (Gregor et al, 2014) and identification of de novo duplication of GPM6A in a patient with learning disability. In fly, M6 shows particularly strong expression in the fly mushroom body (Zappia et al, 2012), which is important for learning and memory processes in Drosophila (McGuire et al, 2001). Another potential mechanism involved in observed region-specific effects could be neurogenesis known to play a critical role in the pathophysiology of depression.…”