The ROR2 tyrosine kinase receptor regulates dendritic spine morphogenesis in hippocampal neurons
The ROR2 tyrosine kinase receptor regulates dendritic spine morphogenesis in hippocampal neurons
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DOI：
10.1016/j.mcn.2015.05.002
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发表时间：
2015-07-01
影响因子：
3.5
通讯作者：
Inestrosa, Nibaldo C.
中科院分区：
文献类型：
--
作者：
Alfaro, Ivan E.;Varela-Nallar, Lorena;Inestrosa, Nibaldo C.
Wnt 信号传导调节突触的发育和功能，并有助于突触分子和形态分化的微调。我们之前已经证明，Wnt5a 激活非经典 Wnt 信号传导，刺激兴奋性海马神经元的突触后分化，促进突触后支架蛋白 PSD-95 的聚集和树突棘的发育。至少三种不同类型的 Wnt 受体与 Wnt5a 信号传导相关：七种跨膜卷曲受体以及酪氨酸激酶受体 Ryk 和 ROR2。我们在此报道，ROR2 分布在海马神经元的树突中，靠近突触接触，并且包含在树突棘突起中。我们证明 ROR2 对于维持培养的海马神经元中的树突棘数量和形态分布是必需的。 ROR2 过表达增加了树突棘生长，但不影响树突棘突起的密度，其形式依赖于其细胞外 Wnt 结合富含半胱氨酸结构域 (CRD) 和激酶结构域。缺乏细胞外CRD的显性失活ROR2的过度表达降低了脊柱密度和蘑菇样脊柱的比例，而缺乏C端和活性激酶结构域的ROR2仅影响脊柱形态。我们的结果表明 ROR2 在海马神经元突触后树突棘的形成和成熟中发挥着至关重要的作用。 (C) 2015 Elsevier Inc. 保留所有权利。
Wnt signaling regulates synaptic development and function and contributes to the fine-tuning of the molecular and morphological differentiation of synapses. We have shown previously that Wnt5a activates non-canonical Wnt signaling to stimulate postsynaptic differentiation in excitatory hippocampal neurons promoting the clustering of the postsynaptic scaffold protein PSD-95 and the development of dendritic spines. At least three different kinds of Wnt receptors have been associated with Wnt5a signaling: seven trans-membrane Frizzled receptors and the tyrosine kinase receptors Ryk and ROR2. We report here that ROR2 is distributed in the dendrites of hippocampal neurons in close proximity to synaptic contacts and it is contained in dendritic spine protrusions. We demonstrate that ROR2 is necessary to maintain dendritic spine number and morphological distribution in cultured hippocampal neurons. ROR2 overexpression increased dendritic spine growth without affecting the density of dendritic spine protrusions in a form dependent on its extracellular Wnt binding cysteine rich domain (CRD) and kinase domain. Overexpression of dominant negative ROR2 lacking the extracellular CRD decreased spine density and the proportion of mushroom like spines, while ROR2 lacking the C-terminal and active kinase domains only affected spine morphology. Our results indicate a crucial role of the ROR2 in the formation and maturation of the postsynaptic dendritic spines in hippocampal neurons. (C) 2015 Elsevier Inc. All rights reserved.