Importin-beta11 regulates synaptic phosphorylated mothers against decapentaplegic, and thereby influences synaptic development and function at the Drosophila neuromuscular junction.
Importin-beta11 regulates synaptic phosphorylated mothers against decapentaplegic, and thereby influences synaptic development and function at the Drosophila neuromuscular junction.
复制标题
DOI：
10.1523/jneurosci.3739-09.2010
复制
发表时间：
2010-04-14
期刊：
影响因子：
--
通讯作者：
Schwarz TL
中科院分区：
文献类型：
--
作者：
Higashi-Kovtun ME;Mosca TJ;Dickman DK;Meinertzhagen IA;Schwarz TL
输入蛋白既在核孔促进底物进入，也在信号运输过程中在细胞质中起作用。在这里，我们描述了果蝇基因输入蛋白-β11的突变，这在以前没有被遗传学分析过。输入蛋白-β11突变体在蛹后期因神经元缺陷而死亡，神经元输入蛋白-β11不仅存在于核孔中，还存在于细胞质和突触中。缺乏输入蛋白-β11的神经元可以存活并正常分化，但表现出离散的缺陷。成虫的光感受器和幼虫的神经肌肉连接处突触传递有缺陷。突变的光感受器轴突在大脑中形成了非常正常的突起和突触终端，但幼虫肌肉上的突触杆更小，但仍含有适当的突触成分。BMP信号是观察到的NMJ缺陷的明显原因。输入蛋白-β11在基因上与BMP通路相互作用，在突变的突触扣上，该通路的一个关键组成部分，磷酸化的母亲抗十足截瘫（pMAD）减少。输入蛋白-β11转基因的神经元表达挽救了这种表型以及其他观察到的神经肌肉表型。尽管突触pMAD丢失，但pMAD在运动神经元核中持续存在，表明pMAD的局部功能存在特异性损伤。通过表达构成活性的I型BMP受体或减少运动神经元的逆行运输，恢复突变末端的pMAD水平，也可以恢复突触强度和形态。因此，输入蛋白-β11功能与BMP通路相互作用，调节突触前必须存在的pMAD库，以保证其正常发育和功能。
Importin proteins act both at the nuclear pore to promote substrate entry and in the cytosol during signal trafficking. Here, we describe mutations in the Drosophila gene importin-β11 which has not previously been analyzed genetically. Mutants of importin-β11 died as late pupae from neuronal defects and neuronal importin-β11 was present not only at nuclear pores but also in the cytosol and at synapses. Neurons lacking importin-β11 were viable and properly differentiated but exhibited discrete defects. Synaptic transmission was defective in adult photoreceptors and at larval neuromuscular junctions. Mutant photoreceptor axons formed grossly normal projections and synaptic terminals in the brain, but synaptic arbors on larval muscles were smaller while still containing appropriate synaptic components. BMP signaling was the apparent cause of the observed NMJ defects. Importin-β11 interacted genetically with the BMP pathway and at mutant synaptic boutons, a key component of this pathway, phosphorylated Mothers Against Decapentaplegic (pMAD), was reduced. Neuronal expression of an importin-β11 transgene rescued this phenotype as well as the other observed neuromuscular phenotypes. Despite the loss of synaptic pMAD, pMAD persisted in motor neuron nuclei, suggesting a specific impairment in the local function of pMAD. Restoring levels of pMAD to mutant terminals via expression of constitutively active type I BMP receptors or by reducing retrograde transport in motor neurons, also restored synaptic strength and morphology. Thus, importin-β11 function interacts with the BMP pathway to regulate a pool of pMAD that must be present at the presynapse for its proper development and function.