ErbB4-Neuregulin Signaling Modulates Synapse Development and Dendritic Arborization through Distinct Mechanisms
ErbB4-Neuregulin Signaling Modulates Synapse Development and Dendritic Arborization through Distinct Mechanisms
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DOI：
10.1074/jbc.m800073200
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发表时间：
2008-11-21
影响因子：
4.8
通讯作者：
El-Husseini, Alaa
中科院分区：
文献类型：
--
作者：
Krivosheya, Daria;Tapia, Lucia;El-Husseini, Alaa
神经调节蛋白-1（NRG 1）/ErbB 4功能的紊乱与精神分裂症有关。受影响的患者表现出这些蛋白质水平的改变，并显示出突触功能减退以及神经元回路的改变。然而，NRG 1/ErbB 4在调节突触成熟和神经元突起形成中的作用尚未得到广泛研究。在这里，我们表明，ErbB 4在兴奋性和抑制性突触后位点的抑制性中间神经元中表达。ErbB 4在突触后的过度表达增加了突触前输入的大小而不是数量。相反，使用shRNA敲低ErbB 4降低了突触前输入的大小，证明了内源性ErbB 4在突触成熟中的特定作用。使用ErbB 4突变体的结构，我们表明，ErbB 4介导的突触成熟需要其胞外结构域，而其酪氨酸激酶活性是这个过程中的一个关键。我们还表明，ErbB 4的耗竭减少了初级神经突的数量，并通过激活ErbB 4的酪氨酸激酶结构域和磷酸肌醇3-激酶途径，使用可溶性形式的NRG 1刺激ErbB 4导致旺盛的树突状树枝化。这些发现表明，NRG 1/ErbB 4信号通过两种不同的机制，分别涉及跨突触信号和酪氨酸激酶活性，差异调节突触成熟和树突状形态。
Perturbations in neuregulin-1 (NRG1)/ErbB4 function have been associated with schizophrenia. Affected patients exhibit altered levels of these proteins and display hypofunction of glutamatergic synapses as well as altered neuronal circuitry. However, the role of NRG1/ErbB4 in regulating synapse maturation and neuronal process formation has not been extensively examined. Here we demonstrate that ErbB4 is expressed in inhibitory interneurons at both excitatory and inhibitory postsynaptic sites. Overexpression of ErbB4 postsynaptically enhances size but not number of presynaptic inputs. Conversely, knockdown of ErbB4 using shRNA decreases the size of presynaptic inputs, demonstrating a specific role for endogenous ErbB4 in synapse maturation. Using ErbB4 mutant constructs, we demonstrate that ErbB4-mediated synapse maturation requires its extracellular domain, whereas its tyrosine kinase activity is dispensable for this process. We also demonstrate that depletion of ErbB4 decreases the number of primary neurites and that stimulation of ErbB4 using a soluble form of NRG1 results in exuberant dendritic arborization through activation of the tyrosine kinase domain of ErbB4 and the phosphoinositide 3-kinase pathway. These findings demonstrate that NRG1/ErbB4 signaling differentially regulates synapse maturation and dendritic morphology via two distinct mechanisms involving trans-synaptic signaling and tyrosine kinase activity, respectively.