Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.
Spinster homolog 2 (spns2) deficiency causes early onset progressive hearing loss.
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DOI：
10.1371/journal.pgen.1004688
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发表时间：
2014-10
期刊：
影响因子：
4.5
通讯作者：
Steel KP
中科院分区：
文献类型：
--
作者：
Chen J;Ingham N;Kelly J;Jadeja S;Goulding D;Pass J;Mahajan VB;Tsang SH;Nijnik A;Jackson IJ;White JK;Forge A;Jagger D;Steel KP
Spns 2在斑马鱼和小鼠中作为鞘氨醇-1-磷酸（S1 P）转运蛋白，分别调节心脏发育和淋巴细胞运输。S1 P是一种具有生物活性的溶血磷脂，在信号传导中具有多种作用。Spns 2的作用机制在哺乳动物中仍然是难以捉摸的。在这里，我们报告说，Spns 2缺陷小鼠迅速失去听觉灵敏度和耳蜗电位（EP）从2至3周龄。我们发现Corti器中的感觉毛细胞进行性变性，但最早的缺陷是EP的下降，这表明外侧壁的功能障碍是原发性病变。在成年突变体的侧壁，我们观察到边缘细胞边界和毛细血管的结构变化，并减少参与EP（Kcnj 10，Kcnq 1，Gjb 2和Gjb 6）的产生的几个关键蛋白的表达，但这些变化可能是次要的。血管纹和毛细血管边界的渗透性正常。我们还发现了Spns 2突变小鼠的局灶性视网膜变性和视网膜毛细血管异常以及前眼缺陷。Spns 2在红细胞、血小板、淋巴管或血管内皮细胞中的靶向失活并不影响听力，但使用Sox 10-Cre等位基因在耳蜗中靶向消融Spns 2产生了与原始突变相似的听觉表型，这表明局部Spns 2表达对哺乳动物的听力至关重要。这些发现表明，Spns 2是EP正常维持所必需的，因此也是正常听觉功能所必需的，并支持S1 P信号在听觉中的作用。进行性听力损失在人类中很常见，但我们对所涉及的分子机制知之甚少。突变小鼠可用于研究这些机制，并揭示了各种不同的异常，这些异常都可能导致相同的结果：耳聋。我们在这里报告了我们对一种新的小鼠品系的发现，该品系的Spns 2基因突变影响了一种称为鞘氨醇-1-磷酸的脂质的释放，这种脂质在体内的几个过程中起着重要作用。我们首次报道，这种分子途径是正常听力所必需的，它通过产生像电池一样的电压差，使耳蜗的感觉毛细胞能够检测到极低水平的声音。如果没有Spns 2基因的正常功能和在内耳局部释放鞘氨醇-1-磷酸，耳蜗中的电压就会下降，导致对声音的敏感性迅速丧失，最终导致完全耳聋。这种基因的人类版本SPNS 2可能与人类耳聋有关，了解其潜在机制为开发这种形式的听力损失的潜在治疗方法提供了机会。
Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively. S1P is a biologically active lysophospholipid with multiple roles in signalling. The mechanism of action of Spns2 is still elusive in mammals. Here, we report that Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old. We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion. In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries, and reduced expression of several key proteins involved in the generation of the EP (Kcnj10, Kcnq1, Gjb2 and Gjb6), but these changes were likely to be secondary. Permeability of the boundaries of the stria vascularis and of the strial capillaries appeared normal. We also found focal retinal degeneration and anomalies of retinal capillaries together with anterior eye defects in Spns2 mutant mice. Targeted inactivation of Spns2 in red blood cells, platelets, or lymphatic or vascular endothelial cells did not affect hearing, but targeted ablation of Spns2 in the cochlea using a Sox10-Cre allele produced a similar auditory phenotype to the original mutation, suggesting that local Spns2 expression is critical for hearing in mammals. These findings indicate that Spns2 is required for normal maintenance of the EP and hence for normal auditory function, and support a role for S1P signalling in hearing. Progressive hearing loss is common in the human population but we know very little about the molecular mechanisms involved. Mutant mice are useful for investigating these mechanisms and have revealed a wide range of different abnormalities that can all lead to the same outcome: deafness. We report here our findings of a new mouse line with a mutation in the Spns2 gene, affecting the release of a lipid called sphingosine-1-phosphate, which has an important role in several processes in the body. For the first time, we report that this molecular pathway is required for normal hearing through a role in generating a voltage difference that acts like a battery, allowing the sensory hair cells of the cochlea to detect sounds at extremely low levels. Without the normal function of the Spns2 gene and release of sphingosine-1-phosphate locally in the inner ear, the voltage in the cochlea declines, leading to rapid loss of sensitivity to sound and ultimately to complete deafness. The human version of this gene, SPNS2, may be involved in human deafness, and understanding the underlying mechanism presents an opportunity to develop potential treatments for this form of hearing loss.
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影响因子：
9.3
作者：
Jabba SV;Oelke A;Singh R;Maganti RJ;Fleming S;Wall SM;Everett LA;Green ED;Wangemann P
通讯作者：
Wangemann P
影响因子：
2.8
作者：
Cable, J;Steel, KP
通讯作者：
Steel, KP
影响因子：
4.8
作者：
Brinkmann, V;Davis, MD;Lynch, KR
通讯作者：
Lynch, KR
影响因子：
3.2
作者：
Crouch, JJ;Sakaguchi, N;Schulte, BA
通讯作者：
Schulte, BA
影响因子：
11.8
作者：
Jung, Bongnam;Obinata, Hideru;Galvani, Sylvain;Mendelson, Karen;Ding, Bi-sen;Skoura, Athanasia;Kinzel, Bernd;Brinkmann, Volker;Rafii, Shahin;Evans, Todd;Hla, Timothy
通讯作者：
Hla, Timothy