Mutations of the mouse ELMO domain containing 1 gene (Elmod1) link small GTPase signaling to actin cytoskeleton dynamics in hair cell stereocilia.
Mutations of the mouse ELMO domain containing 1 gene (Elmod1) link small GTPase signaling to actin cytoskeleton dynamics in hair cell stereocilia.
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DOI：
10.1371/journal.pone.0036074
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发表时间：
2012
期刊：
影响因子：
3.7
通讯作者：
Gagnon LH
中科院分区：
文献类型：
--
作者：
Johnson KR;Longo-Guess CM;Gagnon LH
立体纤毛是从内耳感觉毛细胞的顶端突起的修饰微绒毛，对听力和平衡的机电转导过程是必不可少的。每个毛细胞上充满肌动蛋白的立体纤毛由纤维链连接在一起，形成一个高度花纹的发束。虽然已经鉴定了许多发束的结构成分，但对调控发束发育、形态和维持的信号机制知之甚少。在这里，我们描述了两种自然发生的导致小鼠听力和平衡障碍的等位基因突变，分别称为环绕式(RDA)和环绕式-2J(Rda2J)。定位克隆证实这两种基因都是小鼠Elmo结构域包含1基因(Elmod1)的突变，Elmod1是一种特征不佳的基因，以前没有报道过突变表型。RDA突变是138kb的缺失，包括Elmod1的外显子1-5，而rda2J是Elmod1的外显子3-8的基因内重复。与这些突变相关的耳聋是由耳蜗毛细胞功能障碍引起的，内毛细胞立体纤毛明显延长和融合，外毛细胞立体纤毛进行性退化。哺乳动物Elmo家族蛋白参与激活小的GTP酶的复合体，以调节吞噬和细胞迁移过程中的肌动蛋白细胞骨架。最近发现ELMOD1和ELMOD2是小G蛋白Arf家族的GTP酶激活蛋白(GAP)。我们的发现将ELMOD1缺陷与立体纤毛畸形联系在一起，从而建立了Ras超家族的小调节GTP酶与毛细胞立体纤毛的肌动蛋白细胞骨架动力学之间的联系。
Stereocilia, the modified microvilli projecting from the apical surfaces of the sensory hair cells of the inner ear, are essential to the mechanoelectrical transduction process underlying hearing and balance. The actin-filled stereocilia on each hair cell are tethered together by fibrous links to form a highly patterned hair bundle. Although many structural components of hair bundles have been identified, little is known about the signaling mechanisms that regulate their development, morphology, and maintenance. Here, we describe two naturally occurring, allelic mutations that result in hearing and balance deficits in mice, named roundabout (rda) and roundabout-2J (rda2J). Positional cloning identified both as mutations of the mouse ELMO domain containing 1 gene (Elmod1), a poorly characterized gene with no previously reported mutant phenotypes. The rda mutation is a 138 kb deletion that includes exons 1–5 of Elmod1, and rda2J is an intragenic duplication of exons 3–8 of Elmod1. The deafness associated with these mutations is caused by cochlear hair cell dysfunction, as indicated by conspicuous elongations and fusions of inner hair cell stereocilia and progressive degeneration of outer hair cell stereocilia. Mammalian ELMO-family proteins are known to be involved in complexes that activate small GTPases to regulate the actin cytoskeleton during phagocytosis and cell migration. ELMOD1 and ELMOD2 recently were shown to function as GTPase-activating proteins (GAPs) for the Arf family of small G proteins. Our finding connecting ELMOD1 deficiencies with stereocilia dysmorphologies thus establishes a link between the Ras superfamily of small regulatory GTPases and the actin cytoskeleton dynamics of hair cell stereocilia.
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影响因子：
4.5
作者：
Hertzano R;Elkon R;Kurima K;Morrisson A;Chan SL;Sallin M;Biedlingmaier A;Darling DS;Griffith AJ;Eisenman DJ;Strome SE
通讯作者：
Strome SE
DOI：
10.1523/jneurosci.3998-09.2009
发表时间：
2009-12-16
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Grimsley-Myers CM;Sipe CW;Géléoc GS;Lu X
通讯作者：
Lu X
影响因子：
4.8
作者：
Grimsley, CM;Lu, MJ;Ravichandran, KS
通讯作者：
Ravichandran, KS
影响因子：
3.9
作者：
Donaldson, JG
通讯作者：
Donaldson, JG
DOI：
10.1073/pnas.2334417100
发表时间：
2003-11-25
影响因子：
11.1
作者：
Belyantseva, IA;Boger, ET;Friedman, TB
通讯作者：
Friedman, TB