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First published online 12 April 2006
doi: 10.1242/dev.02361

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

¹ School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA 94720, USA.
² UC Berkeley/UCSF Joint Bioengineering Graduate Program, University of California at Berkeley, Berkeley, CA 94720, USA.
³ Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
⁴ Department of Anatomy and Neurobiology, Morehouse School of Medicine, Atlanta, GA 30310, USA.

^* Author for correspondence (e-mail: xgong{at}berkeley.edu)

Accepted 15 March 2006

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

Key words: Cataract, Connexin, Gap junction, Lens fiber cell

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