Diverse gap junctions modulate distinct mechanisms for fiber cell formation during lens development and cataractogenesis.
Different mutations of alpha3 connexin (Cx46 or Gja8) and alpha8 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 alpha8 connexin mutation that resulted in the expression of alpha8-S50P mutant proteins. Histology studies showed that primary lens fiber cells failed to fully elongate in heterozygous alpha8(S50P/+) embryonic lenses, but not in homozygous alpha8(S50P/S50P), alpha8-/- and alpha3-/- alpha8-/- mutant embryonic lenses. We hypothesized that alpha8-S50P mutant subunits interacted with wild-type alpha3 or alpha8, or with both subunits to affect fiber cell formation. We found that the combination of mutant alpha8-S50P and wild-type alpha8 subunits specifically inhibited the elongation of primary fiber cells, while the combination of alpha8-S50P and wild-type alpha3 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.
Xia
Chun-Hong
CH
School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA 94720, USA.
Liu
Haiquan
H
Cheung
Debra
D
Cheng
Catherine
C
Wang
Eddie
E
Du
Xin
X
Beutler
Bruce
B
Lo
Woo-Kuen
WK
Gong
Xiaohua
X
D000818:Animals; D002386:Cataract / Q000235:genetics* / Q000473:pathology; D002874:Chromosome Mapping; D002875:Chromosomes; D017630:Connexins / Q000235:genetics; D017629:Gap Junctions / Q000235:genetics* / Q000473:pathology / Q000648:ultrastructure; D008040:Genetic Linkage; D006579:Heterozygote; D007908:Lens, Crystalline / Q000196:embryology* / Q000473:pathology* / Q000648:ultrastructure; D008126:Lod Score; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008850:Microphthalmos / Q000235:genetics; D008954:Models, Biological; D020125:Mutation, Missense
D017630:Connexins