An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
An autism-associated variant of Epac2 reveals a role for Ras/Epac2 signaling in controlling basal dendrite maintenance in mice.
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DOI：
10.1371/journal.pbio.1001350
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发表时间：
2012
期刊：
影响因子：
9.8
通讯作者：
Penzes P
中科院分区：
文献类型：
--
作者：
Srivastava DP;Woolfrey KM;Jones KA;Anderson CT;Smith KR;Russell TA;Lee H;Yasvoina MV;Wokosin DL;Ozdinler PH;Shepherd GM;Penzes P
Epac 2破坏损害皮质神经元中的基底（但不是顶端）树突复杂性，并且Epac 2中的自闭症相关突变暗示Ras/Epac 2信号通路在基底树突乔木的主动维持中。树突状乔木的结构决定了神经元的电路连接性、感受野和计算特性，并且树突状结构在几种精神疾病中受损。虽然锥体神经元的顶端和基底树突隔室在功能上是专门化的和差异调节的，但对选择性维持基底树突的机制知之甚少。在这里，我们确定了Ras/Epac 2通路在维持皮质神经元基底树突复杂性中的作用。Epac 2是Ras样小GTap的鸟嘌呤核苷酸交换因子（GEF），在成年小鼠脑中高度富集。我们发现，在体内Epac 2敲低2/3层皮层神经元通过在子宫内电穿孔减少基底树突状结构，和Epac 2敲低在成熟的皮层神经元在体外模拟这种效果。在被诊断患有自闭症的人类受试者中发现的Epac 2罕见编码变体的过表达也损害了基底树突形态。这种突变破坏了Epac 2与Ras的相互作用，Ras的抑制选择性地干扰了基底树突的维持。最后，我们观察到Ras/Epac 2/Rap途径的组分在基底与顶端树突隔室中表现出不同的丰度。这些发现定义了Epac 2在维持基底树突复杂性中使Ras和Rap信号之间的串扰中的作用，以及除了其疾病相关性之外，如何罕见的编码变体可以提供与大脑连接相关的细胞机制的见解。神经元的一个基本特征是其树突的形态，树突是接收和整合来自其他神经元的突触信号的过程。哺乳动物皮层中的神经元表现出两种不同的树突乔木：顶端树突，其延伸远离细胞体，和基底树突，其在细胞体周围局部地精心制作。发育后，神经元必须积极维护这些树突的每一个乔木，以维持其特定的连接。由于一些神经和神经发育障碍与树突状形态的破坏有关，因此了解调节树突状乔木主动维持过程的分子机制至关重要。我们发现，一个特定的分子通路，Ras-Epac 2通路的中断，可以导致在培养的神经元和完整的小鼠大脑中的基底，但不是顶端，树突状乔木显着简化。我们发现，在自闭症患者中发现的Epac 2突变形式也会损害基底树突的维持，并破坏其与Ras的相互作用。我们的研究结果表明，特定的分子通路可以调节不同的树突状区域，并且疾病相关的突变可以告知我们对调节重要生物过程的分子的理解。
Epac2 disruption impairs basal (but not apical) dendrite complexity in cortical neurons, and an autism-associated mutation in Epac2 implicates a Ras/Epac2 signaling pathway in the active maintenance of basal dendritic arbors. The architecture of dendritic arbors determines circuit connectivity, receptive fields, and computational properties of neurons, and dendritic structure is impaired in several psychiatric disorders. While apical and basal dendritic compartments of pyramidal neurons are functionally specialized and differentially regulated, little is known about mechanisms that selectively maintain basal dendrites. Here we identified a role for the Ras/Epac2 pathway in maintaining basal dendrite complexity of cortical neurons. Epac2 is a guanine nucleotide exchange factor (GEF) for the Ras-like small GTPase Rap, and it is highly enriched in the adult mouse brain. We found that in vivo Epac2 knockdown in layer 2/3 cortical neurons via in utero electroporation reduced basal dendritic architecture, and that Epac2 knockdown in mature cortical neurons in vitro mimicked this effect. Overexpression of an Epac2 rare coding variant, found in human subjects diagnosed with autism, also impaired basal dendritic morphology. This mutation disrupted Epac2's interaction with Ras, and inhibition of Ras selectively interfered with basal dendrite maintenance. Finally, we observed that components of the Ras/Epac2/Rap pathway exhibited differential abundance in the basal versus apical dendritic compartments. These findings define a role for Epac2 in enabling crosstalk between Ras and Rap signaling in maintaining basal dendrite complexity, and exemplify how rare coding variants, in addition to their disease relevance, can provide insight into cellular mechanisms relevant for brain connectivity. A fundamental feature of a neuron is the morphology of its dendrites, which are the processes that receive and integrate synaptic signals from other neurons. Neurons in the mammalian cortex exhibit two distinct dendritic arbors: apical dendrites, which extend far from the cell body, and basal dendrites, which elaborate locally around the cell body. After development, neurons must actively maintain each of these dendritic arbors to sustain their specific connectivity. Because several neurological and neurodevelopmental disorders are associated with disruptions in dendritic morphology, it is crucial to understand the molecular mechanisms that regulate the process of active maintenance of dendritic arbors. We find that disruption of a particular molecular pathway, the Ras-Epac2 pathway, can result in dramatic simplification of basal, but not apical, dendritic arbors in both cultured neurons and in the intact mouse brain. We show that a mutant form of Epac2, identified in patients with autism, also impairs basal dendrite maintenance and disrupts its interaction with Ras. Our findings suggest that specific molecular pathways can regulate distinct dendritic regions, and that disease-related mutations can inform our understanding of the molecules that regulate important biological processes.
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