Abstract
BackgroundMembers of the evolutionary conserved Ser/Thr kinase Unc-51 family are key regulatory proteins that control neural development in both vertebrates and invertebrates. Previous studies have suggested diverse functions for the Unc-51 protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport.Methodology/Principal FindingsIn this work, we have investigated the functional significance of Unc-51-mediated vesicle transport in the development of complex brain structures in Drosophila. We show that Unc-51 preferentially accumulates in newly elongating axons of the mushroom body, a center of olfactory learning in flies. Mutations in unc-51 cause disintegration of the core of the developing mushroom body, with mislocalization of Fasciclin II (Fas II), an IgG-family cell adhesion molecule important for axonal guidance and fasciculation. In unc-51 mutants, Fas II accumulates in the cell bodies, calyx, and the proximal peduncle. Furthermore, we show that mutations in unc-51 cause aberrant overshooting of dendrites in the mushroom body and the antennal lobe. Loss of unc-51 function leads to marked accumulation of Rab5 and Golgi components, whereas the localization of dendrite-specific proteins, such as Down syndrome cell adhesion molecule (DSCAM) and No distributive disjunction (Nod), remains unaltered. Genetic analyses of kinesin light chain (Klc) and unc-51 double heterozygotes suggest the importance of kinesin-mediated membrane transport for axonal and dendritic development. Moreover, our data demonstrate that loss of Klc activity causes similar axonal and dendritic defects in mushroom body neurons, recapitulating the salient feature of the developmental abnormalities caused by unc-51 mutations.Conclusions/SignificanceUnc-51 plays pivotal roles in the axonal and dendritic development of the Drosophila brain. Unc-51-mediated membrane vesicle transport is important in targeted localization of guidance molecules and organelles that regulate elongation and compartmentalization of developing neurons.
Highlights
Neurons are highly polarized and compartmentalized cells with an extended axon and highly branched dendrites
We show that unc-51 interacts with the kinesin light chain (Klc) gene in mushroom bodies (MBs) development, and that Klc mutation causes dendritic and axonal defects that are reminiscent of unc-51 mutants
Organization of the Drosophila larval brain To analyze the functions of Unc-51 in neural development in the Drosophila brain, we first focused on the developing MBs at the larval stage (Fig. 1A)
Summary
Neurons are highly polarized and compartmentalized cells with an extended axon and highly branched dendrites. Molecular studies have shown that Unc-51 controls axon formation in the granule cells through the endocytic membrane trafficking pathway via directly binding the synaptic GTPase activation protein (SynGAP) and Syntenin, which is a PDZ domain-containing scaffolding protein that binds Rab GTPase and is involved in endocytic vesicular turnover [14]. Studies in C. elegans have shown that Unc interacts with Unc-14, a RUN domain protein, which regulates kinesin 1-dependent vesicle transport by binding to Unc-16/JIP3/ JSAP1, a cargo adaptor for the kinesin motor proteins [22,23]. Unc-51 phosphorylates Unc-76, which interacts with Synaptotagmin 1 (Syt 1), a synaptic vesicle protein These lines of evidence suggest that Unc-51 regulates the trafficking of early endosomes and their molecular cargos in diverse neuronal cells. Previous studies have suggested diverse functions for the Unc protein, including axonal elongation, growth cone guidance, and synaptic vesicle transport
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