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. ? ? ?
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