Unc-51/ATG1 Controls Axonal and Dendritic Development via Kinesin-Mediated Vesicle Transport in the Drosophila Brain

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.

**背景**：进化保守的丝氨酸/苏氨酸激酶（Ser/Thr kinase）Unc-51家族成员是一类关键调控蛋白，在脊椎动物与无脊椎动物中均参与调控神经发育。既往研究表明，Unc-51蛋白具有多种功能，包括轴突延伸、生长锥导向及突触囊泡转运。
**方法与主要结果**：本研究探讨了Unc-51介导的囊泡转运在果蝇（Drosophila）复杂脑结构发育中的功能意义。我们发现，Unc-51优先富集于果蝇嗅觉学习中枢——蕈形体（mushroom body）的新生延伸轴突中。unc-51基因突变会导致发育中蕈形体的核心结构解体，并伴随成束蛋白Fasciclin II（Fas II）的定位异常——该分子属于IgG家族细胞黏附分子，对轴突导向和束化至关重要。在unc-51突变体中，Fas II会在神经元胞体、萼叶（calyx）以及近端柄部富集。此外，我们发现unc-51突变会导致蕈形体和触角叶（antennal lobe）中的树突出现异常过度延伸。丧失unc-51功能会导致Rab5和高尔基体组分显著富集，而树突特异性蛋白——如唐氏综合征细胞黏附分子（Down syndrome cell adhesion molecule, DSCAM）与非均等分离蛋白（No distributive disjunction, Nod）——的定位则无明显变化。对驱动蛋白轻链（kinesin light chain, Klc）与unc-51双杂合子的遗传分析表明，驱动蛋白介导的膜转运对轴突和树突发育至关重要。此外，我们的数据显示，丧失Klc活性会在蕈形体神经元中引发类似的轴突和树突缺陷，重现了unc-51突变所导致的发育异常核心特征。
**结论与意义**：Unc-51在果蝇脑的轴突和树突发育中发挥关键调控作用。Unc-51介导的膜囊泡转运，对调控发育神经元延伸与区室化的导向分子及细胞器的靶向定位至关重要。