Abi2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory
Abi2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis, and deficits in learning and memory
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DOI：
10.1128/mcb.24.24.10905-10922.2004
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发表时间：
2004-12-01
影响因子：
5.3
通讯作者：
Pendergast, AM
中科院分区：
文献类型：
--
作者：
Grove, M;Demyanenko, G;Pendergast, AM
Abi相互作用蛋白（Abi）家族与Abi酪氨酸激酶和Rac GTPase的信号通路有关。Abi蛋白定位于肌动蛋白的突起膜结构聚合位点，并在体外调节肌动蛋白动力学。在这里，我们证明了Abi2在体内调节细胞的形态发生和迁移。小鼠abi2的纯合子缺失在眼睛和大脑中产生异常表型，这是abi2表达最高的组织。在缺乏Abi2的情况下，眼内继发性晶状体纤维定向和迁移存在缺陷，在增殖、分化和凋亡方面没有可检测到的缺陷。这些表型与Abi2在体外发育中的晶状体粘附连接和新生上皮细胞粘附连接的定位一致。RNA干扰对Abi表达的下调会破坏粘附结的形成，并与波动蛋白成核促进因子的下调相关。Abi2缺失还会导致新皮质和海马的细胞迁移缺陷，树突棘形态和密度异常，以及严重的短期和长期记忆缺陷。这些发现支持Abi2在粘附连接和树突棘的细胞骨架动力学调控中的作用，这对细胞间连接、细胞形态发生和认知功能至关重要。
The Abl-interactor (Abi) family of adaptor proteins has been linked to signaling pathways involving the Abi tyrosine kinases and the Rac GTPase. Abi proteins localize to sites of actin polymerization in protrusive membrane structures and regulate actin dynamics in vitro. Here we demonstrate that Abi2 modulates cell morphogenesis and migration in vivo. Homozygous deletion of murine abi2 produced abnormal phenotypes in the eye and brain, the tissues with the highest Abi2 expression. In the absence of Abi2, secondary lens fiber orientation and migration were defective in the eye, without detectable defects in proliferation, differentiation, or apoptosis. These phenotypes were consistent with the localization of Abi2 at adherens junctions in the developing lens and at nascent epithelial cell adherens junctions in vitro. Downregulation of Abi expression by RNA interference impaired adherens junction formation and correlated with downregulation of the Wave actin-nucleation promoting factor. Loss of Abi2 also resulted in cell migration defects in the neocortex and hippocampus, abnormal dendritic spine morphology and density, and severe deficits in short- and long-term memory. These findings support a role for Abi2 in the regulation of cytoskeletal dynamics at adherens junctions and dendritic spines, which is critical for intercellular connectivity, cell morphogenesis, and cognitive functions.