Tropomodulin isoforms utilize specific binding functions to modulate dendrite development.
Tropomodulin isoforms utilize specific binding functions to modulate dendrite development.
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DOI：
10.1002/cm.21304
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发表时间：
2016-06
期刊：
影响因子：
--
通讯作者：
Kostyukova AS
中科院分区：
文献类型：
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作者：
Gray KT;Suchowerska AK;Bland T;Colpan M;Wayman G;Fath T;Kostyukova AS
Tropomodulins（Tmods）帽F-肌动蛋白尖端，并在神经系统疾病的大脑中改变表达。Tmods在神经元中的功能研究很少，它们在神经系统疾病中的作用完全未知。在本文中，我们表明，Tmod 1和Tmod 2，而不是Tmod 3，是树突的复杂性和树突棘形态的正调节。Tmod 1增加了细胞体远端的树突分支和丝状伪足/细刺的数量。Tmod 2增加接近细胞体的树突分支和成熟树突棘的数量。Tmods利用两个肌动蛋白结合位点和两个原肌球蛋白（Tpm）结合位点来帽F-肌动蛋白。过表达的Tmods与破坏的Tpm结合位点表明，Tmod 1和Tmod 2差异利用其Tpm和肌动蛋白结合位点，影响形态。Tmod 1的Tpm结合位点的破坏废除了过表达表型。相反，突变的Tmod 2的过表达引起与野生型过表达相同的表型。邻近连接测定表明突变的Tmods与野生型Tmods类似地穿梭。我们的数据开始揭示Tmods在神经发育中的作用以及Tmods改变神经形态的机制。这些观察结果与在几种神经系统疾病中发现的Tmod表达改变相结合，也表明Tmod表达失调可能参与这些疾病的病理学。
Tropomodulins (Tmods) cap F-actin pointed ends and have altered expression in the brain in neurological diseases. The function of Tmods in neurons has been poorly studied and their role in neurological diseases is entirely unknown. In this paper we show that Tmod1 and Tmod2, but not Tmod3, are positive regulators of dendritic complexity and dendritic spine morphology. Tmod1 increases dendritic branching distal from the cell body and the number of filopodia/thin spines. Tmod2 increases dendritic branching proximal to the cell body and the number of mature dendritic spines. Tmods utilize two actin-binding sites and two tropomyosin (Tpm)-binding sites to cap F-actin. Overexpression of Tmods with disrupted Tpm-binding sites indicates that Tmod1 and Tmod2 differentially utilize their Tpm- and actin-binding sites to affect morphology. Disruption of Tmod1’s Tpm-binding sites abolished the overexpression phenotype. In contrast, overexpression of the mutated Tmod2 caused the same phenotype as wild type overexpression. Proximity ligation assays indicate that the mutated Tmods are shuttled similarly to wild type Tmods. Our data begins to uncover the roles of Tmods in neural development and the mechanism by which Tmods alter neural morphology. These observations in combination with altered Tmod expression found in several neurological diseases also suggest that dysregulation of Tmod expression may be involved in the pathology of these diseases.