Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development and cataractogenesis

Abstract

Different mutations of α3 connexin (Cx46 or Gja8) andα8 connexin (Cx50 or Gja8), subunits of lens gap junction channels, cause a variety of cataracts via unknown mechanisms. We identified a dominant cataractous mouse line (L1), caused by a missense α8 connexin mutation that resulted in the expression of α8-S50P mutant proteins. Histology studies showed that primary lens fiber cells failed to fully elongate in heterozygous α8S50P/+ embryonic lenses, but not in homozygous α8S50P/S50P, α8-/- andα3-/- α8-/- mutant embryonic lenses. We hypothesized that α8-S50P mutant subunits interacted with wild-typeα3 or α8, or with both subunits to affect fiber cell formation. We found that the combination of mutant α8-S50P and wild-type α8 subunits specifically inhibited the elongation of primary fiber cells, while the combination of α8-S50P and wild-type α3 subunits disrupted the formation of secondary fiber cells. Thus, this work provides the first in vivo evidence that distinct mechanisms, modulated by diverse gap junctions, control the formation of primary and secondary fiber cells during lens development. This explains why and how different connexin mutations lead to a variety of cataracts. The principle of this explanation can also be applied to mutations of other connexin isoforms that cause different diseases in other organs.