Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.
Defective Gpsm2/Gα(i3) signalling disrupts stereocilia development and growth cone actin dynamics in Chudley-McCullough syndrome.
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DOI：
10.1038/ncomms14907
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发表时间：
2017-04-07
影响因子：
16.6
通讯作者：
Montcouquiol M
中科院分区：
文献类型：
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作者：
Mauriac SA;Hien YE;Bird JE;Carvalho SD;Peyroutou R;Lee SC;Moreau MM;Blanc JM;Geyser A;Medina C;Thoumine O;Beer-Hammer S;Friedman TB;Rüttiger L;Forge A;Nürnberg B;Sans N;Montcouquiol M
GPSM 2突变导致Chudley-McCullough综合征（CMCS），这是一种常染色体隐性遗传神经系统疾病，其特征是早发性感觉神经性耳聋和脑异常。在这里，我们表明，突变的小鼠直系同源GPSM 2影响肌动蛋白丰富的静纤毛延长听觉和前庭毛细胞，造成耳聋和平衡缺陷。G蛋白亚基Gαi3是Gpsm 2的一个有据可查的伙伴，参与了延长过程，它的缺失也会导致听力障碍。我们发现Gpsm 2在静纤毛的尖端定义了一个大约200 nm的纳米结构域，这种定位需要Gαi3，肌球蛋白15和whirlin的存在。使用单分子跟踪，我们报告说，Gpsm 2的损失导致减少生长和破坏肌动蛋白在神经元生长锥的动力学。我们的研究结果阐明了CMCS的病因学，并强调了Gpsm 2/Gαi3在上皮和神经元组织中调节肌动蛋白动力学的新分子作用。GPSM 2的突变导致一种罕见的疾病，其特征是耳聋和大脑异常。在这里，作者表明，Gpsm 2与异源三聚体G蛋白亚基，whirlin和肌球蛋白马达形成分子复合物，以调节神经元和听觉毛细胞静纤毛中的肌动蛋白动力学。
Mutations in GPSM2 cause Chudley-McCullough syndrome (CMCS), an autosomal recessive neurological disorder characterized by early-onset sensorineural deafness and brain anomalies. Here, we show that mutation of the mouse orthologue of GPSM2 affects actin-rich stereocilia elongation in auditory and vestibular hair cells, causing deafness and balance defects. The G-protein subunit Gαi3, a well-documented partner of Gpsm2, participates in the elongation process, and its absence also causes hearing deficits. We show that Gpsm2 defines an ∼200 nm nanodomain at the tips of stereocilia and this localization requires the presence of Gαi3, myosin 15 and whirlin. Using single-molecule tracking, we report that loss of Gpsm2 leads to decreased outgrowth and a disruption of actin dynamics in neuronal growth cones. Our results elucidate the aetiology of CMCS and highlight a new molecular role for Gpsm2/Gαi3 in the regulation of actin dynamics in epithelial and neuronal tissues. Mutations in GPSM2 cause a rare disease characterized by deafness and brain abnormalities. Here the authors show that Gpsm2 forms a molecular complex with a heterotrimeric G-protein subunit, whirlin and a myosin motor to regulate actin dynamics in neurons and auditory hair cell stereocilia.