Lens intercellular communication, connexins and cataract

描述：人类透镜连接蛋白基因突变导致白内障。在小鼠中靶向缺失这些连接蛋白也会产生白内障，为研究提供了动物模型。透镜含有三种不同的连接蛋白，Cx43、Cx46和Cx 50，它们具有不同的表达模式和翻译后修饰。Cx43在透镜上皮中产生，但不在透镜纤维中产生，Cx46在纤维分化期间合成，Cx 50存在于两种细胞类型中。其中之一，Cx 50的缺失，由于出生后细胞分裂的短暂减少，导致轻度白内障和较小的晶状体。Cx46的缺失不会改变透镜细胞的生长，但会导致严重的白内障。尽管Cx43基因敲除和Cx43/Cx 50双基因敲除小鼠在新生儿死亡前经历正常的胚胎透镜发育，但目前对Cx43在成年透镜体内平衡中的作用知之甚少，因为敲除小鼠在出生时死于心脏异常。通过基因敲入用Cx46替换Cx 50挽救了白内障表型，但没有减少细胞分裂，证明了这些不同间隙连接蛋白的独特体内功能。此外，在杂合子敲入动物中Cx46和Cx 50的不适当混合产生显性白内障，同时保持正常的透镜大小。目前的建议的目的是进一步定义细胞功能，需要在透镜中的连接通信，并更好地了解如何在间隙连接蛋白的多样性影响细胞间的通信，通过追求以下三个具体目标：1。表征 影响出生后透镜有丝分裂的Cx 50的特定功能特性。2.产生并表征在Cx46基因座上表达Cx 50的小鼠。3.确定纤维成熟过程中Cx46和Cx 50裂解的功能后果。对比透镜连接蛋白的功能差异不仅将提供对人类透镜发育和白内障发生的机制性洞察，而且还将提供缝隙连接通讯的特定方面如何控制细胞分裂和稳态的一般模型。

DESCRIPTION: 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 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.