Lens intercellular communication, connexins and cataract

人类晶状体连接蛋白基因的突变会导致白内障。在小鼠体内靶向删除这些连接蛋白 还会产生白内障，为研究提供动物模型。晶状体含有三种不同的连接蛋白， Cx43、Cx46和CX50具有不同的表达模式和翻译后修饰。Cx43是 Cx46在晶状体上皮细胞中合成，而不是在晶状体纤维中合成，在纤维分化过程中合成 CX50在两种细胞类型中都存在。其中一个基因CX50的缺失会导致轻度白内障和较小的白内障 晶状体由于出生后细胞分裂的一过性减少。Cx46的缺失不改变晶状体细胞的生长， 但也会导致严重的白内障。目前，人们对Cx43在成人晶状体内稳态中的作用知之甚少 AS基因敲除小鼠出生时死于心脏异常，尽管Cx43基因敲除和Cx43/CX50基因敲除加倍 基因敲除的小鼠经历正常的胚胎晶状体发育，直到新生儿死亡。更换CX50 Cx46通过基因敲击挽救了白内障的表型，但不是细胞分裂的减少， 展示了这些不同的缝隙连接蛋白在体内的独特功能。此外， CX46和CX50在杂合子敲击动物中的不适当混合会产生显性白内障，而 保持正常的镜头大小。当前提案的目标是进一步定义细胞功能， 需要在晶状体中进行连接通信，并更好地了解缝隙连接中的多样性 蛋白质通过追求以下三个特定目标来影响细胞间的通讯：1.表征 影响出生后晶状体有丝分裂的CX50的特殊功能特性。2.生成和表征 在Cx46基因座上表达CX50的小鼠。3.确定Cx46和Cx46的功能后果 CX50在纤维成熟过程中发生裂解。对比晶状体连接蛋白的功能差异不仅会 提供对人类晶状体发育和白内障发生的机械性洞察，但也将提供 缝隙连接通信的特定方面如何控制细胞分裂和 动态平衡。

Mutations in the human lens connexin genes cause cataracts. Targeted deletion of these connexins in mice also produces cataract, providing animal models for study. The lens contains three different connexins, Cx43, Cx46 and Cx50 that have distinct expression patterns and post-translational modifications. Cx43 is made in the lens epithelium but not the lens fibers, Cx46 is synthesized in during fiber differentiation, and Cx50 is present in both cell types. Deletion of one of these, Cx50, results in mild cataracts and smaller lenses due to a transient reduction in postnatal cell division. Deletion of Cx46 does not alter lens cell growth, but does produce severe cataracts. Currently, little is known about the role of Cx43 in adult lens homeostasis as knockout mice die at birth from cardiac abnormalities, although Cx43 knockout and Cx43/Cx50 double knockout mice undergo normal embryonic lens development up until neonatal death. Replacement of Cx50 with Cx46 by genetic knockin rescues the cataract phenotype, but not the reduced cell division, demonstrating the distinctive in vivo functions of these different gap junction proteins. In addition, the inappropriate mixing of Cx46 and Cx50 in heterozygous knockin animals produces dominant cataracts while maintaining normal lens size. The objective of the current proposal is to further define cellular functions that require junctional communication in the lens, and to better understand how the diversity in gap junctional proteins influences intercellular communication by pursuing the following three specific aims: 1. Characterize the specific functional properties of Cx50 that influence postnatal lens mitosis. 2. Generate and characterize mice that express Cx50 on the Cx46 gene locus. 3. Determine the functional consequences of Cx46 and Cx50 cleavage during fiber maturation. Contrasting the functional differences in lens connexins will not only provide mechanistic insight into human lens development and cataractogenesis, but will also provide a general model for how specific aspects of gap junctional communication control cell division and homeostasis.