GEFT调节晶状体上皮细胞分化的机制研究
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摘要
GEFT是Rho家族小GTP酶特定的鸟嘌呤核苷酸交换因子,在成人易兴奋组织包括脑、心脏和骨骼肌中有高水平的表达。以前研究发现GEFT在成年小鼠海马和小脑中表达,过度表达GEFT蛋白质能导致神经轴突和树突重塑。这一发现促使本文探索GEFT在其它组织中的表达,这些组织与神经系统有着共同的祖先,特别是在视觉系统中。
本文通过免疫组织化学法分析GEFT特定蛋白的表达,我们观察到在小鼠的晚期胚胎眼部,GEFT在成神经细胞层和分化中的晶状体纤维中表达水平最高,并在后生角膜上皮、晶状体上皮细胞,及整个视网膜中均有表达。
在N/N1003A兔晶状体上皮细胞中,GEFT的外源表达诱导晶状体纤维细胞的分化,体现在细胞的伸长和眼球系统形成,同时还导致β-晶状体蛋白和晶状体蛋白微丝表达显著增强。GEFT转染晶状体上皮细胞还导致由RAC-1介导的αA-、αB-、βB-、γC-、和γF-晶状体蛋白启动子活性上调,这种活性部分依赖于Rac1的核定位。此外,药物抑制Rac1可阻断GEFT诱导的N/N1003A晶状体纤维分化和β-晶状体蛋白在体外小鼠晶状体移植体中的表达。
这些结果第一次表明了GEFT在晶状体细胞分化和小鼠眼发育中的作用,揭示了GEFT调控晶状体的分化和眼的发育基于依赖Rac1的机制。
The Rho-family of small GTPase specific guanine nucleotide exchange factor, GEFT, is expressed at high levels in adult human excitable tissues including the brain, heart, and skeletal muscle. Previously, we demonstrated that GEFT is specifically expressed in the adult mouse hippocampus and cerebellum, and that overexpression of this protein can result in neurite and dendrite remodeling. This finding prompted us to explore the expression of GEFT in other tissues, which share common developmental ancestry to the nervous system, specifically the ocular system.
Using immunohistochemical analysis specific for GEFT protein expression, we observed the highest ocular expression of GEFT occurring in the neuroblastic layer and differentiating lens fibers of the late-stage mouse embryo, and in the postnatal corneal epithelium, lens epithelium, and throughout the retina. Exogenous expression of GEFT in N/N1003A
rabbit lens epithelial cells induced lens fiber differentiation as reflected by cell elongation and lentoid formation, as well as a strong increase inβ-crystallin and filensin expression. Moreover, transfection of lens epithelial cells with GEFT resulted in a Rac-1 mediated up-regulation ofαA-,αB-,βB-,γC-,orγF-crystallin promoter activities that is in part dependent on the nuclear localization of Rac1. Furthermore, pharmacological inhibition of Racl blocked GEFT-induced N/N1003A lens fiber differentiation andβB-crystallin expression in ex vivo mouse lens explants.
These results demonstrate for the first time a role for GEFT in lens cell differentiation and mouse eye development. Moreover, GEFT regulation of lens differentiation and eye development occurs through a Rac1-dependent mechanism.
本文通过免疫组织化学法分析GEFT特定蛋白的表达,我们观察到在小鼠的晚期胚胎眼部,GEFT在成神经细胞层和分化中的晶状体纤维中表达水平最高,并在后生角膜上皮、晶状体上皮细胞,及整个视网膜中均有表达。
在N/N1003A兔晶状体上皮细胞中,GEFT的外源表达诱导晶状体纤维细胞的分化,体现在细胞的伸长和眼球系统形成,同时还导致β-晶状体蛋白和晶状体蛋白微丝表达显著增强。GEFT转染晶状体上皮细胞还导致由RAC-1介导的αA-、αB-、βB-、γC-、和γF-晶状体蛋白启动子活性上调,这种活性部分依赖于Rac1的核定位。此外,药物抑制Rac1可阻断GEFT诱导的N/N1003A晶状体纤维分化和β-晶状体蛋白在体外小鼠晶状体移植体中的表达。
这些结果第一次表明了GEFT在晶状体细胞分化和小鼠眼发育中的作用,揭示了GEFT调控晶状体的分化和眼的发育基于依赖Rac1的机制。
The Rho-family of small GTPase specific guanine nucleotide exchange factor, GEFT, is expressed at high levels in adult human excitable tissues including the brain, heart, and skeletal muscle. Previously, we demonstrated that GEFT is specifically expressed in the adult mouse hippocampus and cerebellum, and that overexpression of this protein can result in neurite and dendrite remodeling. This finding prompted us to explore the expression of GEFT in other tissues, which share common developmental ancestry to the nervous system, specifically the ocular system.
Using immunohistochemical analysis specific for GEFT protein expression, we observed the highest ocular expression of GEFT occurring in the neuroblastic layer and differentiating lens fibers of the late-stage mouse embryo, and in the postnatal corneal epithelium, lens epithelium, and throughout the retina. Exogenous expression of GEFT in N/N1003A
rabbit lens epithelial cells induced lens fiber differentiation as reflected by cell elongation and lentoid formation, as well as a strong increase inβ-crystallin and filensin expression. Moreover, transfection of lens epithelial cells with GEFT resulted in a Rac-1 mediated up-regulation ofαA-,αB-,βB-,γC-,orγF-crystallin promoter activities that is in part dependent on the nuclear localization of Rac1. Furthermore, pharmacological inhibition of Racl blocked GEFT-induced N/N1003A lens fiber differentiation andβB-crystallin expression in ex vivo mouse lens explants.
These results demonstrate for the first time a role for GEFT in lens cell differentiation and mouse eye development. Moreover, GEFT regulation of lens differentiation and eye development occurs through a Rac1-dependent mechanism.
引文
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