The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function
The S1P2 sphingosine 1-phosphate receptor is essential for auditory and vestibular function
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DOI：
10.1016/j.heares.2006.06.016
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发表时间：
2006-10-01
期刊：
影响因子：
2.8
通讯作者：
Miller, Marian L.
中科院分区：
文献类型：
--
作者：
MacLennan, A. John;Benner, Shannon J.;Miller, Marian L.
鞘氨醇 I-磷酸 (SIP) 是一种内源性生长因子，对许多不同的细胞类型具有有效作用。大多数这些效应是通过激活 G 蛋白偶联受体家族中的一个或多个而产生的。 S1P(2) 受体可以介导 SIP 诱导的多种培养细胞的增殖、分化和存活。然而，由于 S1P2 的普遍表达以及在 S1P(2) 敲除小鼠的初步分析中未能检测到任何解剖学异常，鉴定 S1P2 的基本体内功能受到了阻碍。我们在此报告，所有 S1P(2) 基因敲除小鼠从出生后第 22 天起就出现严重耳聋，并且大约一半的小鼠表现出随着衰老而逐渐丧失前庭功能。从解剖学上讲，听觉系统和前庭系统似乎发育正常，但随后就会退化。与听力相关的形态缺陷在出生后 3 周首次被发现，表现为 Corti/Nuel 空间器官的变形。到一岁时，阶梯介质内的结构发生了巨大的变化。 S1P(2) 基因敲除小鼠还表现出与前庭损伤一致的耳石丧失。目前的数据首次表明 SIP 信号在体内、听觉和前庭功能中发挥着关键作用。这些数据进一步证实，SIP 信号传导是通过 S1P(2) 受体发生的，并且是必不可少的。对这些系统的结构维护的贡献，提高了这种信号传导的适当有针对性的增强可能被证明在临床上有益的可能性。 (c) 2006 Elsevier B.V. 保留所有权利。
Sphingosine I-phosphate (SIP) is an endogenous growth factor with potent effects on many different cell types. Most of these effects are produced by activation of one or more of a family of G-protein coupled receptors. The S1P(2) receptor can mediate SIP-induced proliferation, differentiation and survival in a wide variety of cells in culture. However, identifying essential in vivo functions for S1P2 has been hampered by its ubiquitous expression and the failure to detect any anatomical abnormalities in initial analyses Of S1P(2) knockout mice. We report here that all S1P(2) knockout mice are profoundly deaf from postnatal day 22 and approximately half display a progressive loss of vestibular function with aging. Anatomically, both the auditory and vestibular systems appear to develop normally but then degrade. Morphological defects associated with hearing are first detected at 3 weeks postnatal as deformations of the organ of Corti/Nuel's space. By one year of age structures within the scala media are dramatically altered. The S1P(2) knockout mice also display a loss of otoconia consistent with the vestibular impairment. The present data are the first to indicate that SIP signaling plays critical roles, in vivo, in auditory and vestibular functions. The data further establish that the SIP signaling occurs through the S1P(2) receptor and makes an essential. contribution to the structural maintenance of these systems, raising the possibility that properly targeted enhancement of this signaling may prove to be clinically beneficial. (c) 2006 Elsevier B.V. All rights reserved.