Disruption of α3Connexin Gene Leads to Proteolysis and Cataractogenesis in Mice

Three connexin genes have been reported to be expressed in the lens. The a1 connexin (Cx43) has been detected in mouse lens epithelial cells (Yancey et al., Xiaohua Gong,* En Li,† George Klier,* Qingling Huang,‡ Ying Wu,* Hong Lei,† Nalin M. Kumar,* Joseph Horwitz,‡ and Norton B. Gilula*§ 1992). Both a3 (Cx46) and a8 (Cx50) connexin have been detected in the elongating primary fibers, as well as in *Department of Cell Biology The Scripps Research Institute the secondary fibers during lens development, and they are colocalized to the same gap junction plaques (Paul La Jolla, California 92037 †Cardiovascular Research Center, MGH et al., 1991). The most abundant proteins in the vertebrate lens are Harvard Medical School Charlestown, Massachusetts 02129 crystallins, which account for more than 90% of the lens-soluble proteins (Bloemendal, 1981; Harding and ‡Jules Stein Eye Institute at UCLA Los Angeles, California 90095 Crabbe, 1984). Crystallins from mammalian lenses are divided into three major classes: a-, b-, and g-crystallins. Lens transparency results from the suprastructural organization of the lens that is created by both plasma Summary membrane components and cytoplasmic proteins, including the crystallins. However, the molecular mechaGap junction channels formed by a3 (Cx46) and a8 nisms by which this organization is generated and main(Cx50) connexin provide pathways for communication tained are not well understood. between the fiber cells in the normal transparent lens. The objective of this study has been to determine the To determine the specific role of a3 connexin in vivo, contribution of cell–cell communication via gap junction the a3 connexin gene was disrupted in mice. Although channels in lens function. For this purpose, we perturbed the absence of a3 connexin had no obvious influence the cell–cell communication network in the mouse lens on the early stages of lens formation and the differentiby selectively eliminating the a3 connexin protein, one of ation of lens fibers, mice homozygous for thedisrupted the two connexins in the lens fibers, by a gene disruption a3 gene developed nuclear cataracts that were assoapproach and investigated the consequence of the abciated with the proteolysis of crystallins. This study sence of a3 connexin protein on lens development and establishes the importance of gap junctions in mainfunction. taining normal lens transparency by providing a cell–cell signaling pathway or structural component for the proper organization of lens membrane and cytoplasResults mic proteins.