Gap junction-mediated intercellular coupling is higher in the equatorial region of the lens than at either pole, a property believed to be essential for lens transparency. We show that fibroblast growth factor (FGF) upregulates gap junctional intercellular dye transfer in primary cultures of embryonic chick lens cells without detectably increasing either gap junction protein (connexin) synthesis or assembly. Insulin and insulin-like growth factor 1, as potent as FGF in inducing lens cell differentiation, had no effect on gap junctions. FGF induced sustained activation of extracellular signal-regulated kinase (ERK) in lens cells, an event necessary and sufficient to increase gap junctional coupling. We also identify vitreous humor as an in vivo source of an FGF-like intercellular communication-promoting activity and show that FGF-induced ERK activation in the intact lens is higher in the equatorial region than in polar and core fibers. These findings support a model in which regional differences in FGF signaling through the ERK pathway lead to the asymmetry in gap junctional coupling required for proper lens function. Our results also identify upregulation of intercellular communication as a new function for sustained ERK activation and change the current paradigm that ERKs only negatively regulate gap junction channel activity.

译文

间隙连接介导的细胞间耦合在晶状体的赤道区域比在任一极处都要高,这一特性被认为对晶状体透明性至关重要。我们显示,成纤维细胞生长因子 (FGF) 在胚胎雏鸡晶状体细胞的原代培养物中上调间隙连接细胞间染料转移,而不会明显增加间隙连接蛋白 (连接蛋白) 的合成或组装。胰岛素和胰岛素样生长因子1在诱导晶状体细胞分化方面与FGF一样有效,对间隙连接没有影响。FGF诱导晶状体细胞中细胞外信号调节激酶 (ERK) 的持续激活,这是增加间隙连接偶联所必需且足以的事件。我们还将玻璃体液鉴定为FGF样细胞间通讯促进活性的体内来源,并表明完整晶状体中FGF诱导的ERK激活在赤道区域高于极性和核心纤维。这些发现支持一个模型,在该模型中,通过ERK途径的FGF信号传导的区域差异导致适当的晶状体功能所需的间隙连接耦合的不对称性。我们的结果还确定了细胞间通讯的上调是持续ERK激活的新功能,并改变了ERKs仅负调节间隙连接通道活性的当前范例。

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