INTERCELLULAR COMMUNICATION IN THE LENS

Summary

Principal Investigator: Lisa Ebihara
Affiliation: Rosalind Franklin University of Medicine and Science
Country: USA
Abstract: The lens is an avascular, syncytial organ that is dependent on the intercellular communication for the maintenance of transparency and tissue homeostasis. Two different gap junctional proteins, Connexin 46 (Cx48) and Connexin 50 (Cx50), have been identified in lens fiber cells. The overall objective of this research proposal is to understand the role of jap junctional communication in the lens. Detailed knowledge of the functional properties of gap junctional communication in the lens. Detailed knowledge of the functional properties of gap junctional proteins in the lens is important if we are to understand how these connexins contribute to lens homeostasis and how cataracts arise. There are three specific aims: 1) To study the biophysical properties of cloned lens gap junctional proteins and to localize the molecular determinants of permeability and gating of the gap junctional channels. We will investigate the molecular basis for differences in the selectivity of Cx43, Cx50 and Cx46 gap junctional channels for charged molecules by expressing wild-type and mutant connexin constructs in Xenopus oocytes and transfected cell lines. 2) To examine the effects of connexin mutations associated with congenital cataracts. We will further examine the effects of the mutations on gap junctional channel activity in transfected N2A cells using a dual whole cell patch clamp technique. In a parallel series of experiments, we will use immunocytochemical techniques to determine the pattern of expression of wild-type and mutant connexins in transfected cells. 3) To explore the role of junctional hemi-gap junctional channels in the lens under physiological and pathophysiological conditions. To determine if differentiating fiber cells express channels that have the properties of hemi-gap junctional channels, we will examine macroscopic currents in freshly isolated, newly differentiating mouse fiber cells, using electrophysiological techniques. We will perform similar experiments on isolated, differentiating fiber cells from homozygous Cx46(-/-) and Cx50 (-/-) mice to demonstrate that connexins underlie the hemichannel-like currents. In addition, we will examine several possible mechanisms for hemichannel activation.
Funding Period: 1994-06-01 - 2008-11-30
more information: NIH RePORT

Top Publications

  1. ncbi An aberrant sequence in a connexin46 mutant underlies congenital cataracts
    Peter J Minogue
    Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA
    J Biol Chem 280:40788-95. 2005
  2. ncbi A novel GJA8 mutation is associated with autosomal dominant lamellar pulverulent cataract: further evidence for gap junction dysfunction in human cataract
    A Arora
    J Med Genet 43:e2. 2006
  3. ncbi Structural determinants for the differences in voltage gating of chicken Cx56 and Cx45.6 gap-junctional hemichannels
    Jun-Jie Tong
    Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science/Chicago Medical School, 3333 Green Bay Road North, Chicago, IL 60064, USA
    Biophys J 91:2142-54. 2006
  4. ncbi Role of the N-terminus in permeability of chicken connexin45.6 gap junctional channels
    Lixian Dong
    Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
    J Physiol 576:787-99. 2006
  5. ncbi Transgenic overexpression of connexin50 induces cataracts
    June Chung
    Department of Pediatrics, University of Chicago, IL 60637, USA
    Exp Eye Res 84:513-28. 2007
  6. ncbi A novel connexin50 mutation associated with congenital nuclear pulverulent cataracts
    A Arora
    UCL Institute of Ophthalmology, London, UK
    J Med Genet 45:155-60. 2008
  7. ncbi A mutant connexin50 with enhanced hemichannel function leads to cell death
    Peter J Minogue
    Department of Pediatrics, Section of Hematology Oncology, University of Chicago, Chicago, Illinois 60637, USA
    Invest Ophthalmol Vis Sci 50:5837-45. 2009
  8. ncbi The GJA8 allele encoding CX50I247M is a rare polymorphism, not a cataract-causing mutation
    Jochen Graw
    Helmholtz Center Munich German Research Center for Environmental Health, Institute of Developmental Genetics, D 85764 Neuherberg, Germany
    Mol Vis 15:1881-5. 2009

Scientific Experts

  • June Chung
  • Peter J Minogue
  • Lisa Ebihara
  • A Arora
  • Eric C Beyer
  • Viviana M Berthoud
  • Jochen Graw
  • Jun Jie Tong
  • A R Webster
  • P J Minogue
  • L Ebihara
  • A T Moore
  • E C Beyer
  • D M Hunt
  • V M Berthoud
  • X Liu
  • Lixian Dong
  • Jun-Jie Tong
  • Xiaoqin Liu
  • Thomas Illig
  • Norman Klopp
  • Anthony T Moore
  • David M Hunt
  • Anita Arora
  • Isabelle Russell-Eggitt
  • Werner Schmidt
  • Jessica Rodriguez
  • I Russel-Eggitt
  • P K Addison
  • Hui Li
  • M A Reddy
  • S S Bhattacharya
  • J R Ainsworth
  • Barbara M Vertel

Detail Information

Publications8

  1. ncbi An aberrant sequence in a connexin46 mutant underlies congenital cataracts
    Peter J Minogue
    Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA
    J Biol Chem 280:40788-95. 2005
    ..These results suggest a novel mechanism in which a mutation causes disease by generating a motif that leads to retention within the synthetic/secretory pathway...
  2. ncbi A novel GJA8 mutation is associated with autosomal dominant lamellar pulverulent cataract: further evidence for gap junction dysfunction in human cataract
    A Arora
    J Med Genet 43:e2. 2006
    ..The cataract likely results from lack of gap junction function. The lack of function was associated with improper targeting to the plasma membrane, most probably due to protein misfolding...
  3. ncbi Structural determinants for the differences in voltage gating of chicken Cx56 and Cx45.6 gap-junctional hemichannels
    Jun-Jie Tong
    Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science/Chicago Medical School, 3333 Green Bay Road North, Chicago, IL 60064, USA
    Biophys J 91:2142-54. 2006
    ..6 and Cx56 hemichannels; the first transmembrane-spanning domain, M1, is an important determinant of macroscopic current magnitude; R9 and E43 are also determinants of single channel conductance and rectification...
  4. ncbi Role of the N-terminus in permeability of chicken connexin45.6 gap junctional channels
    Lixian Dong
    Department of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, North Chicago, IL 60064, USA
    J Physiol 576:787-99. 2006
    ..6. These data suggest that the N-terminus plays a critical role in determining many of biophysical properties of Cx45.6 gap junctional channels, including molecular permeability and voltage gating...
  5. ncbi Transgenic overexpression of connexin50 induces cataracts
    June Chung
    Department of Pediatrics, University of Chicago, IL 60637, USA
    Exp Eye Res 84:513-28. 2007
    ....
  6. ncbi A novel connexin50 mutation associated with congenital nuclear pulverulent cataracts
    A Arora
    UCL Institute of Ophthalmology, London, UK
    J Med Genet 45:155-60. 2008
    ..To screen for mutations of connexin50 (Cx50)/GJA8 in a panel of patients with inherited cataract and to determine the cellular and functional consequences of the identified mutation...
  7. ncbi A mutant connexin50 with enhanced hemichannel function leads to cell death
    Peter J Minogue
    Department of Pediatrics, Section of Hematology Oncology, University of Chicago, Chicago, Illinois 60637, USA
    Invest Ophthalmol Vis Sci 50:5837-45. 2009
    ..To determine the consequences of expression of a novel connexin50 (CX50) mutant identified in a child with congenital total cataracts...
  8. ncbi The GJA8 allele encoding CX50I247M is a rare polymorphism, not a cataract-causing mutation
    Jochen Graw
    Helmholtz Center Munich German Research Center for Environmental Health, Institute of Developmental Genetics, D 85764 Neuherberg, Germany
    Mol Vis 15:1881-5. 2009
    ..The aim of this study was the genetic, cellular, and physiological characterization of a connexin50 (CX50) variant identified in a child with congenital cataracts...