Dominant cataracts result from incongruous mixing of wild-type lens connexins.
Gap junctions are composed of proteins called connexins (Cx) and facilitate both ionic and biochemical modes of intercellular communication. In the lens, Cx46 and Cx50 provide the gap junctional coupling needed for homeostasis and growth. In mice, deletion of Cx46 produced severe cataracts, whereas knockout of Cx50 resulted in significantly reduced lens growth and milder cataracts. Genetic replacement of Cx50 with Cx46 by knockin rescued clarity but not growth. By mating knockin and knockout mice, we show that heterozygous replacement of Cx50 with Cx46 rescued growth but produced dominant cataracts that resulted from disruption of lens fiber morphology and crystallin precipitation. Impedance measurements revealed normal levels of ionic gap junctional coupling, whereas the passage of fluorescent dyes that mimic biochemical coupling was altered in heterozygous knockin lenses. In addition, double heterozygous knockout lenses retained normal growth and clarity, whereas knockover lenses, where native Cx46 was deleted and homozygously knocked into the Cx50 locus, displayed significantly deficient growth but maintained clarity. Together, these findings suggest that unique biochemical modes of gap junctional communication influence lens clarity and lens growth, and this biochemical coupling is modulated by the connexin composition of the gap junction channels.
Martinez-Wittinghan
Francisco J
FJ
Department of Physiology and Biophysics, State University of New York, Stony Brook 11794, USA.
Sellitto
Caterina
C
Li
Leping
L
Gong
Xiaohua
X
Brink
Peter R
PR
Mathias
Richard T
RT
White
Thomas W
TW
D000818:Animals; D002386:Cataract / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology; D002450:Cell Communication / Q000235:genetics; D048429:Cell Size / Q000235:genetics; D017630:Connexins / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003459:Crystallins / Q000378:metabolism; D004195:Disease Models, Animal; D005136:Eye Proteins / Q000235:genetics / Q000378:metabolism; D005260:Female; D005456:Fluorescent Dyes; D017629:Gap Junctions / Q000235:genetics / Q000378:metabolism*; D006579:Heterozygote; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism; D007908:Lens, Crystalline / Q000254:growth & development / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics*; D000099264:Connexin 50
D017630:Connexins; D003459:Crystallins; D005136:Eye Proteins; D005456:Fluorescent Dyes; D007473:Ion Channels; D000099264:Connexin 50; C082917:GJA3 protein, human