Scaffold Protein X11α Interacts with Kalirin-7 in Dendrites and Recruits It to Golgi Outposts
Scaffold Protein X11α Interacts with Kalirin-7 in Dendrites and Recruits It to Golgi Outposts
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DOI：
10.1074/jbc.m114.587709
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发表时间：
2014-12-19
影响因子：
4.8
通讯作者：
Penzes, Peter
中科院分区：
文献类型：
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作者：
Jones, Kelly A.;Eng, Andrew G.;Penzes, Peter
哺乳动物前脑中的锥体神经元通过树突树接收突触输入，而树突棘是大多数兴奋性突触的位置。树突棘结构对大脑发育和可塑性至关重要。Kalirin-7是小GTPase Rac1的鸟嘌呤核苷酸交换因子，是树突脊柱重构的关键调节因子。钾素-7的亚细胞定位被认为是调节其在神经元中的功能的重要因素。酵母双杂交筛选已鉴定出衔接蛋白X11为kalirin-7的相互作用伙伴。在这里，我们发现钾素-7和X11在大脑中形成复合物，这种相互作用是由钾素-7的C端介导的。Kalirin-7和X11共同定位于培养皮层神经元的兴奋性突触。利用光漂白后荧光恢复的延时成像，我们发现X11存在于突触后密度的可移动部分。X11也定位于树突中的高尔基体前哨，其过表达诱导高尔基体前哨中钾素-7的清除和钾素-7的积累。此外，过表达X11的神经元显示出更细的脊髓。这些数据支持了kalirin-7在树突中定位和功能调节的新机制，为神经元可塑性的信号通路提供了见解。解剖突触结构可塑性的分子机制将提高我们对神经精神和神经退行性疾病的理解，因为kalilin -7与精神分裂症和阿尔茨海默病有关。
Pyramidal neurons in the mammalian forebrain receive their synaptic inputs through their dendritic trees, and dendritic spines are the sites of most excitatory synapses. Dendritic spine structure is important for brain development and plasticity. Kalirin-7 is a guanine nucleotide-exchange factor for the small GTPase Rac1 and is a critical regulator of dendritic spine remodeling. The subcellular localization of kalirin-7 is thought to be important for regulating its function in neurons. A yeast two-hybrid screen has identified the adaptor protein X11 as an interacting partner of kalirin-7. Here, we show that kalirin-7 and X11 form a complex in the brain, and this interaction is mediated by the C terminus of kalirin-7. Kalirin-7 and X11 co-localize at excitatory synapses in cultured cortical neurons. Using time-lapse imaging of fluorescence recovery after photobleaching, we show that X11 is present in a mobile fraction of the postsynaptic density. X11 also localizes to Golgi outposts in dendrites, and its overexpression induces the removal of kalirin-7 from spines and accumulation of kalirin-7 in Golgi outposts. In addition, neurons overexpressing X11 displayed thinner spines. These data support a novel mechanism of regulation of kalirin-7 localization and function in dendrites, providing insight into signaling pathways underlying neuronal plasticity. Dissecting the molecular mechanisms of synaptic structural plasticity will improve our understanding of neuropsychiatric and neurodegenerative disorders, as kalirin-7 has been associated with schizophrenia and Alzheimer disease.