Rab8, POSH, and TAK1 regulate synaptic growth in a Drosophila model of frontotemporal dementia.
Bottom Line: Expression of Rab8 rescued overgrowth phenotypes generated by CHMP2B(Intron5).We identify novel roles for endosomal JNK-scaffold POSH (Plenty-of-SH3s) and a JNK kinase kinase, TAK1, in regulating growth activation in Rab8 mutants.Our data uncover Rab8, POSH, and TAK1 as regulators of synaptic growth responses and point to recycling endosome as a key compartment for synaptic growth regulation during neurodegenerative processes.
Affiliation: Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK.Show MeSH
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Mentions: Previous studies demonstrated that the JNK–activator protein-1 (AP-1) signal transduction pathway plays a major role in the activation of overgrowth of the larval NMJ (Collins et al., 2006) gating the activity of the TGF-β pathway when synaptic growth is seen to be substantially above that of a wild-type synapse (Berke et al., 2013). In previous studies, genetic activation of TGF-β signaling alone at the larval NMJ has resulted in only modest increases in synapse growth (Sweeney and Davis, 2002; Rawson et al., 2003; McCabe et al., 2004; Berke et al., 2013). The JNK–AP-1 pathway has been identified as an evolutionarily conserved stress-activated kinase pathway that can be activated in response to a range of both endogenous and environmental stimuli in neurons. In response to stimuli, a kinase cascade, acting through JNK, activates a series of downstream targets, including AP-1, comprised of hetero- and/or homo-dimers of Fos and Jun (Antoniou and Borsello, 2012). Expression of a dominant-negative Fos (FosDN) can be used to inhibit JNK/AP-1 signaling (Eresh et al., 1997; Collins et al., 2006). Neuronal expression of FosDN, under the control of the panneuronal driver n-Syb–Gal4 or motor neuron driver OK6-Gal4, does not affect NMJ growth in a wild-type background (Fig. 6, A and B). However, expression of FosDN both panneuronally and in motor neurons alone is sufficient to completely alleviate synaptic overgrowth in Rab8 mutants (Fig. 6, A and B). In addition, although heterozygous mutants of puc (puckered), a negative regulator of JNK that is transcriptionally activated by JNK signaling, display no perturbation to NMJ size, heterozygous combinations of pucE69 and Rab81 have an increase in synaptic bouton number comparable to that seen in Rab8 trans-heterozygote combinations (Fig. 6, A and B). We then asked whether AP-1 transcriptional activity was elevated in Rab8 mutant neurons. Puc is a transcriptional target of AP-1 signaling (Martín-Blanco et al., 1998). Using a Puc-LacZ enhancer trap as a transcriptional reporter, we confirm the JNK–AP-1 signaling pathway to be more active in the motor neuronal nuclei of Rab8 mutant larvae compared with wild type (Fig. 6, C and D). Collectively, this genetic evidence indicates JNK signaling to be essential for the synaptic overgrowth observed in Rab8 mutants.
Affiliation: Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK Department of Biology and Hull York Medical School, University of York, Heslington, York YO10 5DD, England, UK.