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

Different mutations of alpha 3 connexin (Cx46 or Gja8) and alpha 8 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 alpha 8 connexin mutation that resulted in the expression of alpha 8-S50P mutant proteins. Histology studies showed that primary lens fiber cells failed to fully elongate in heterozygous alpha 8(S50P/+) embryonic lenses, but not in homozygous alpha 8(S50P/S50P), alpha 8(-/-) and alpha 3(-/-) alpha 8(-/-) mutant embryonic lenses. We hypothesized that alpha 8-S50P mutant subunits interacted with wild-type alpha 3 or alpha 8, or with both subunits to affect fiber cell formation. We found that the combination of mutant alpha 8-S50P and wild-type alpha 3 subunits specifically inhibited the elongation of primary fiber cells, while the combination of alpha 8-S50P and wild-type alpha 3 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.