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

Chun Hong Xia, Haiquan Liu, Debra Cheung, Catherine Cheng, Eddie Wang, Xin Du, Bruce Beutler, Woo Kuen Lo, Xiaohua Gong

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Different mutations of α3 connexin (Cx46 or Gja8) and α8 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 α8 connexin mutation that resulted in the expression of α8-S50P mutant proteins. Histology studies showed that primary lens fiber cells failed to fully elongate in heterozygous α8S50P/+ embryonic lenses, but not in homozygous α8S50P/S50P, α8-/- and α3-/- α8-/- mutant embryonic lenses. We hypothesized that α8S50P mutant subunits interacted with wild-type α3 or α8, or with both subunits to affect fiber cell formation. We found that the combination of mutant α8-S50P and wild-type α8 subunits specifically inhibited the elongation of primary fiber cells, while the combination of α8-S50P and wild-type α3 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.

Original languageEnglish (US)
Pages (from-to)2033-2040
Number of pages8
JournalDevelopment
Volume133
Issue number10
DOIs
StatePublished - May 1 2006

Keywords

  • Cataract
  • Connexin
  • Gap junction
  • Lens fiber cell

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

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