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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Xia, C-H; Liu, H; Cheung, D; Cheng, C; Wang, E; Du, X; Beutler, B; Lo, W-K; Gong, X

Published Date

  • May 2006

Published In

Volume / Issue

  • 133 / 10

Start / End Page

  • 2033 - 2040

PubMed ID

  • 16611690

Pubmed Central ID

  • 16611690

Electronic International Standard Serial Number (EISSN)

  • 1477-9129

International Standard Serial Number (ISSN)

  • 0950-1991

Digital Object Identifier (DOI)

  • 10.1242/dev.02361

Language

  • eng