The influence of glycogen synthase kinase 3 in limiting cell addition in the mammalian ear
The influence of glycogen synthase kinase 3 in limiting cell addition in the mammalian ear
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DOI：
10.1002/dneu.20635
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发表时间：
2008-07-01
影响因子：
3
通讯作者：
Corwin, Jeffrey T.
中科院分区：
文献类型：
--
作者：
Lu, Zhenjie;Corwin, Jeffrey T.
在内耳的前庭器官中，出生后早期细胞增殖能力的下降似乎是哺乳动物特有的毛细胞再生受限的原因。我们已经研究了细胞增殖下降的时间过程及其通过糖原合成酶激酶-3（GSK 3）的潜在调节。我们的免疫印迹显示，出生后小鼠椭圆囊上皮中的非活性GSK 3 β减少，而E-钙粘蛋白和活性形式的GSK 3 α和GSK 3 β各自增加。在培养的椭圆囊上皮细胞中，LiCl和SB-216763对GSK 3的药理学抑制在一系列出生后年龄范围内增加了细胞增殖。LiCl处理还导致β-连环蛋白和Snail水平升高，E-钙粘蛋白表达降低。显性阴性GSK 3 β的转染以细胞自主方式增强了这些上皮细胞的增殖，而野生型GSK 3 β的过表达显着降低了这种增殖。这些测量和实验操作的证据表明，活性和非活性形式的平衡GSK 3有助于确定哺乳动物前庭支持细胞是否会增殖;当非活性GSK 3占主导地位时，在早期发育期间允许增殖，并逐渐抑制增殖，从而限制毛细胞再生的能力，因为在出生后成熟的第一周期间更多的GSK 3变得活性。(c)2008 Wiley Periodicals，Inc.
in the vestibular organs of the inner ear, an early postnatal decline in the capacity for cell proliferation appears to be responsible for limits to hair cell regeneration that are unique to mammals. We have investigated the time course of that decline in cell proliferation and its potential regulation by glycogen synthase kinase-3 (GSK3). Our immunoblots have revealed that inactive GSK3 beta decreases postnatally in the murine utricular epithelium, as E-cadherin and the active forms of GSK3 alpha and GSK3 beta each increase. In cultured utricular epithelia, pharmacological inhibition of GSK3 by LiCl and SB-216763 increased cell proliferation across a range of postnatal ages. LiCl treatments also led to increased levels of beta-catenin and Snail and decreased expression of E-cadherin. Transfection with a dominant-negative GSK3 beta enhanced proliferation in these epithelia in a cell-autonomous manner, while overexpression of wild-type GSK3 beta markedly reduced it. The evidence from these measurements and experimental manipulations indicates that the balance of active and inactive forms of GSK3 helps to determine whether mammalian vestibular supporting cells will proliferate; permitting proliferation during early development when inactive GSK3 predominates and progressively inhibiting proliferation, and thereby limiting the capacity for hair cell regeneration as more GSK3 becomes active during the first week of postnatal maturation. (c) 2008 Wiley Periodicals, Inc.