Disruption ofGja8(α8 connexin) in mice leads to microphthalmia associated with retardation of lens growth and lens fiber maturation

The development of the vertebrate lens utilizes a sophisticated cell-cell communication network via gap junction channels, which are made up of at least three connexin isoforms, α8 (Cx50), α3 (Cx46) and α1 (Cx43), and which are encoded by three different genes. In a previous study, we reported that, with a disruption of Gja3 (α3 connexin), mice developed nuclear cataracts with a normal sized lens. We show that Gja8tm1 (α8–/–) mice develop microphthalmia with small lenses and nuclear cataracts, while the α8 heterozygous (+/–) mice have relatively normal eyes and lenses. A comparative study of these α3 and α8 knockout mice showed that the protein levels of both α3 and α8 were independently regulated and there was no compensation for either the α3 or α8 protein from the wild-type allele when the other allele was disrupted. More interestingly, western blotting data indicated that the presence of α8 in the lens nucleus is dependent on α3 connexin, but not vice versa. The staining of the knock-in lacZ reporter gene showed the promoter activity of α8 connexin is much higher than that of α3 connexin in embryonic lenses and in adult lens epithelium. More importantly, a delayed denucleation process was observed in the interior fibers of the α8–/– lenses. Therefore, α8 connexin is required for proper fiber cell maturation and control of lens size.