The Drosophila fragile X gene negatively regulates neuronal elaboration and synaptic differentiation
The Drosophila fragile X gene negatively regulates neuronal elaboration and synaptic differentiation
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DOI：
10.1016/j.cub.2004.09.085
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发表时间：
2004-10-26
期刊：
影响因子：
9.2
通讯作者：
Broadie, K
中科院分区：
文献类型：
--
作者：
Pan, LY;Zhang, YQ;Broadie, K
脆性X综合征(FRAX)是遗传性智力低下最常见的形式。这种疾病是由编码RNA结合翻译调节因子FMRP[1-4]的脆性X智力低下1(Fmr1)基因沉默引起的。在FRAX患者和fmr1基因敲除小鼠中，FMRP的丢失导致突触后树突棘更密集和形态改变[5-7]。此前，我们建立了果蝇FRAX模型，并表明dFMRP作为Futsch/MAP1B的负翻译调节因子，负调控外周神经肌肉接头(NMJ)的突触分支和结构细化[8]。在这里，我们研究dFMRP在中央大脑中的作用，重点放在蘑菇体(MB)，学习和记忆中心[9，10]。在MB神经元中，dFMRP双向调节多个水平的结构结构，包括胞体突起形成、树突细化、轴突分支和突触形成。果蝇fmr1(Dfmr)缺失突变神经元表现出更复杂的结构，包括过度生长、过度分支和异常突触形成。相反，dFMRP的过度表达简化了神经元结构，导致生长不足、分支不足和突触分化丧失。对超微结构dfmr突变神经元的研究显示，突触突触突起扩大且不规则，突触小泡密集堆积。综上所述，这些数据表明，dFMRP是周围和中枢神经系统中神经元结构和突触分化的强有力的负调控因子。
Fragile X Syndrome (FraX) is the most common form of inherited mental retardation. The disease is caused by the silencing of the fragile X mental retardation 1 (fmr1) gene, which encodes the RNA binding translational regulator FMRP [1-4]. In FraX patients and fmr1 knockout mice, loss of FMRP causes denser and morphologically altered postsynaptic dendritic spines [5-7]. Previously, we established a Drosophila FraX model and showed that dFMRP acts as a negative translational regulator of Futsch/MAP1B and negatively regulates synaptic branching and structural elaboration in the peripheral neuromuscular junction (NMJ) [8]. Here, we investigate the role of dFMRP in the central brain, focusing on the mushroom body (MB), the learning and memory center [9, 10]. In MB neurons, dFMRP bidirectionally regulates multiple levels of structural architecture, including process formation from the soma, dendritic elaboration, axonal branching, and synaptogenesis. Drosophila fmr1 (dfmr) null mutant neurons display more complex architecture, including over-growth, overbranching, and abnormal synapse formation. In contrast, dFMRP overexpression simplifies neuronal structure, causing undergrowth, underbranching, and loss of synapse differentiation. Studies of ultrastructural dfmr mutant neurons reveal enlarged and irregular synaptic boutons with dense accumulation of synaptic vesicles. Taken together, these data show that dFMRP is a potent negative regulator of neuronal architecture and synaptic differentiation in both peripheral and central nervous systems.