Graduate School of Life and Environmental Sciences, University of Tsukuba, Tsukuba, Japan.
PLoS One. 2011 May 12;6(5):e19632. doi: 10.1371/journal.pone.0019632.
Members 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 FINDINGS: In 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/SIGNIFICANCE: Unc-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.
进化保守的丝氨酸/苏氨酸激酶 Unc-51 家族的成员是控制脊椎动物和无脊椎动物神经发育的关键调节蛋白。先前的研究表明 Unc-51 蛋白具有多种功能，包括轴突伸长、生长锥导向和突触小泡运输。
方法/主要发现：在这项工作中，我们研究了 Unc-51 介导的囊泡运输在果蝇复杂大脑结构发育中的功能意义。我们表明，Unc-51 优先积累在蘑菇体新伸长的轴突中，蘑菇体是苍蝇嗅觉学习的中心。unc-51 突变导致正在发育的蘑菇体核心解体，Fas II（一种 IgG 家族细胞粘附分子，对轴突导向和聚集很重要）定位错误。在 unc-51 突变体中，Fas II 积累在细胞体、心冠和近端花梗中。此外，我们表明，unc-51 突变导致蘑菇体和触角叶中的树突过度生长。unc-51 功能丧失导致 Rab5 和高尔基体成分的明显积累，而树突特异性蛋白，如唐氏综合征细胞粘附分子（DSCAM）和 No distributive disjunction（Nod）的定位保持不变。对 kinesin 轻链（Klc）和 unc-51 双杂合子的遗传分析表明，kinesin 介导的膜运输对轴突和树突发育很重要。此外，我们的数据表明 Klc 活性的丧失会导致蘑菇体神经元中类似的轴突和树突缺陷，再现了 unc-51 突变引起的发育异常的显著特征。
结论/意义：Unc-51 在果蝇大脑的轴突和树突发育中起着关键作用。Unc-51 介导的膜囊泡运输对于调节发育中神经元伸长和区室化的导向分子和细胞器的靶向定位很重要。
