BIOLOGY OF LENS INTERCELLULAR COMMUNICATION

Summary

Principal Investigator: Eric C Beyer
Abstract: Mutations of two genes that encode gap junction proteins that are expressed in the lens (CX46 and CX50) are among the most frequent genetic causes of congenital cataracts. Our previous studies of a variety of cataract-associated connexin mutants (predominantly through expression in Xenopus oocytes or transfected mammalian cell lines) have shown that most of these connexin mutants are not functional (and sometimes act as dominant negative inhibitors of their wild type counterparts). Moreover, many of these mutants exhibit one of two types of abnormal cellular behaviors: (1) they accumulate in cytoplasmic inclusions and appear to be resistant to degradation or (2) they do not traffic properly to the plasma membrane and localize within the secretory pathway. We hypothesize that lens cells expressing mutant connexins that form cytoplasmic inclusions or are retained within the secretory pathway will exhibit unique abnormalities due to abnormal interactions (or lack of interactions) of the connexin mutants with lens-specific proteins causing their retention, altered abundance, or decreased function. Experiments are proposed to study representative members of each class of connexin mutants in lens cells (of chicken embryos, stably transfected lens epithelial cell lines, or lenses of mice carrying connexin mutations). A repertoire of microscopy, cell biological and biochemical approaches will be used to address two central questions: " What are the fates of the mutant connexins in the lens? " What are the consequences of expression of the mutant connexins upon other lens components? The data obtained from these studies are likely to have broad implications towards understanding cataract formation in general, since similar cellular abnormalities (formation of inclusions and retention in the biosynthetic pathway) have also been observed for many other cataract-associated mutant proteins.
Funding Period: 1990-01-01 - 2015-06-30
more information: NIH RePORT

Top Publications

  1. pmc 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
  2. pmc Autophagy: a pathway that contributes to connexin degradation
    Alexandra Lichtenstein
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    J Cell Sci 124:910-20. 2011
  3. pmc Structural organization of intercellular channels II. Amino terminal domain of the connexins: sequence, functional roles, and structure
    Eric C Beyer
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    Biochim Biophys Acta 1818:1823-30. 2012
  4. pmc Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization
    Tekla D Smith
    Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Atlanta, GA 30022, USA
    J Membr Biol 245:221-30. 2012
  5. pmc Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function
    Oscar Jara
    Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile
    Mol Biol Cell 23:3299-311. 2012
  6. pmc An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract
    G Senthil Kumar
    Department of Genetics, Dr ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
    Exp Eye Res 110:136-41. 2013
  7. pmc Connexin mutants and cataracts
    Eric C Beyer
    Department of Pediatrics, University of Chicago Chicago, IL, USA
    Front Pharmacol 4:43. 2013
  8. pmc A connexin50 mutant, CX50fs, that causes cataracts is unstable, but is rescued by a proteasomal inhibitor
    Peter J Minogue
    Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA
    J Biol Chem 288:20427-34. 2013
  9. pmc Connexin50D47A decreases levels of fiber cell connexins and impairs lens fiber cell differentiation
    Viviana M Berthoud
    Department of Pediatrics, University of Chicago, Chicago, Illinois
    Invest Ophthalmol Vis Sci 54:7614-22. 2013
  10. pmc Different domains are critical for oligomerization compatibility of different connexins
    Agustin D Martinez
    Centro Interdisciplinario de Neurociencias de Valparaíso, Departamento de Neurociencias, Universidad de Vaparaíso, Valparaíso 2360102, Chile
    Biochem J 436:35-43. 2011

Detail Information

Publications21

  1. pmc 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
    ..To identify the gene responsible for autosomal dominant lamellar pulverulent cataract in a four-generation British family and characterise the functional and cellular consequences of the mutation...
  2. pmc Autophagy: a pathway that contributes to connexin degradation
    Alexandra Lichtenstein
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    J Cell Sci 124:910-20. 2011
    ..These results demonstrate that autophagy can regulate cellular levels of wild-type connexins and imply that the persistence of accumulations of CX50P88S results from insufficient degradation capacity of constitutive autophagy...
  3. pmc Structural organization of intercellular channels II. Amino terminal domain of the connexins: sequence, functional roles, and structure
    Eric C Beyer
    Department of Pediatrics, University of Chicago, Chicago, IL 60637, USA
    Biochim Biophys Acta 1818:1823-30. 2012
    ..This article is part of a Special Issue entitled: The Communicating junctions, composition, structure and characteristics...
  4. pmc Cytoplasmic amino acids within the membrane interface region influence connexin oligomerization
    Tekla D Smith
    Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, Emory University School of Medicine, Whitehead Biomedical Research Building, Atlanta, GA 30022, USA
    J Membr Biol 245:221-30. 2012
    ....
  5. pmc Critical role of the first transmembrane domain of Cx26 in regulating oligomerization and function
    Oscar Jara
    Centro Interdisciplinario de Neurociencias de Valparaíso, Universidad de Valparaiso, Valparaiso, Chile
    Mol Biol Cell 23:3299-311. 2012
    ..Moreover, Cx26 oligomerization appears dependent on transient TM1 dimerization as an intermediate step...
  6. pmc An MIP/AQP0 mutation with impaired trafficking and function underlies an autosomal dominant congenital lamellar cataract
    G Senthil Kumar
    Department of Genetics, Dr ALM Post Graduate Institute of Basic Medical Sciences, University of Madras, Chennai, India
    Exp Eye Res 110:136-41. 2013
    ..They emphasize the importance of AQP0 for maintenance of lens transparency and identify a critical residue that is conserved among aquaporins, but has not previously been associated with disease-associated replacement...
  7. pmc Connexin mutants and cataracts
    Eric C Beyer
    Department of Pediatrics, University of Chicago Chicago, IL, USA
    Front Pharmacol 4:43. 2013
    ..They may also contribute to our understanding of the mechanisms of disease due to connexin mutations in other tissues...
  8. pmc A connexin50 mutant, CX50fs, that causes cataracts is unstable, but is rescued by a proteasomal inhibitor
    Peter J Minogue
    Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA
    J Biol Chem 288:20427-34. 2013
    ..The efficacy of epoxomicin in restoring function suggests that protease inhibition might have therapeutic value for this and other diseases caused by mutants with similar defects. ..
  9. pmc Connexin50D47A decreases levels of fiber cell connexins and impairs lens fiber cell differentiation
    Viviana M Berthoud
    Department of Pediatrics, University of Chicago, Chicago, Illinois
    Invest Ophthalmol Vis Sci 54:7614-22. 2013
    ..To elucidate the lens abnormalities caused by a substitution at this position, we studied No2 mice, which carry the Cx50D47A mutation and parallel the human pathology...
  10. pmc Different domains are critical for oligomerization compatibility of different connexins
    Agustin D Martinez
    Centro Interdisciplinario de Neurociencias de Valparaíso, Departamento de Neurociencias, Universidad de Vaparaíso, Valparaíso 2360102, Chile
    Biochem J 436:35-43. 2011
    ..However, motifs in different domains may determine oligomerization compatibility in members of different connexin subfamilies...
  11. pmc Different consequences of cataract-associated mutations at adjacent positions in the first extracellular boundary of connexin50
    Jun Jie Tong
    Dept of Physiology and Biophysics, Rosalind Franklin University of Medicine and Science, 3333 Green Bay Road, North Chicago, IL 60064, USA
    Am J Physiol Cell Physiol 300:C1055-64. 2011
    ....
  12. pmc 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...
  13. pmc Transgenic overexpression of connexin50 induces cataracts
    June Chung
    Department of Pediatrics, University of Chicago, IL 60637, USA
    Exp Eye Res 84:513-28. 2007
    ....
  14. pmc 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...
  15. pmc Cataracts are caused by alterations of a critical N-terminal positive charge in connexin50
    Bettina C Thomas
    Department of Pediatrics, University of Chicago, Chicago, Illinois 60637 1470, USA
    Invest Ophthalmol Vis Sci 49:2549-56. 2008
    ....
  16. pmc An intact connexin N-terminus is required for function but not gap junction formation
    John W Kyle
    Department of Medicine, Section of Cardiology, University of Chicago, Chicago, IL 60637, USA
    J Cell Sci 121:2744-50. 2008
    ..We conclude that as much as half the length of the connexin N-terminus can be deleted without affecting formation of gap junction plaques, but an intact N-terminus is required for hemichannel gating and intercellular communication...
  17. pmc Oxidative stress, lens gap junctions, and cataracts
    Viviana M Berthoud
    Department of Pediatrics, University of Chicago, Chicago, Illinois 60637, USA
    Antioxid Redox Signal 11:339-53. 2009
    ..These observations suggest that oxidative stress-induced damage to connexins (and consequent altered intercellular communication) may contribute to cataract formation...
  18. pmc The cytoplasmic accumulations of the cataract-associated mutant, Connexin50P88S, are long-lived and form in the endoplasmic reticulum
    Alexandra Lichtenstein
    Department of Pediatrics, Section of Hematology Oncology, University of Chicago, Chicago, IL 60637 1470, USA
    Exp Eye Res 88:600-9. 2009
    ..The persistence of these particles in the lens may cause light scattering and the pulverulent cataracts observed in affected individuals...
  19. pmc The N terminus of connexin37 contains an alpha-helix that is required for channel function
    John W Kyle
    Department of Medicine Section of Cardiology, University of Chicago, Chicago, Illinois 60637 1470, USA
    J Biol Chem 284:20418-27. 2009
    ..Taken together, our data suggest that the alpha-helical structure of the connexin37 N terminus may be dispensable for protein localization, but it is required for channel and hemichannel function...
  20. pmc 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...
  21. pmc Roles and regulation of lens epithelial cell connexins
    Viviana M Berthoud
    Department of Pediatrics and Pritzker School of Medicine, University of Chicago, Chicago, IL 60637, United States Electronic address
    FEBS Lett 588:1297-303. 2014
    ..Cx43 and Cx50 hemichannels and gap junction channels are regulated by multiple different agents. Lens epithelial cell connexins contribute to both normal lens physiology and pathology. ..

Research Grants31

  1. INTERCELLULAR COMMUNICATION IN THE LENS
    Lisa Ebihara; Fiscal Year: 2013
    ..abstract_text> ..
  2. Cataractogenesis, Connexin Mutants, and Genetic Modifiers
    Xiaohua Gong; Fiscal Year: 2013
    ..The information will be important for developing a new strategy to effectively prevent or delay nuclear cataracts, which account for about one-third of age-related cataracts. ..
  3. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..
  4. POST TRANSCRIPTIONAL CONTROL OF GENE EXPRESSION IN THE LENS (LENS GENE EXPRESSION
    SALIL LACHKE; Fiscal Year: 2013
    ..Since mutation of one lens-specific RG component, TDRD7, causes human cataracts, these studies will also provide fundamental information about cataract formation. ..
  5. STRUCTURE AND DYNAMICS OF CONNEXIN26 GAP JUNCTIONS
    Gina E Sosinsky; Fiscal Year: 2013
    ..The proposed research is significant because results will be useful in defining better drugs and other therapeutics that potentially ameliorate connexin-related diseases. ..
  6. STRUCTURAL ANALYSIS OF GAP JUNCTION TRAFFICKING
    Gina E Sosinsky; Fiscal Year: 2013
    ..We investigate the connexin43 trafficking process using an imaging based approach examining the hierarchy of connexin43 phosphorylation events and where within the cell cycle, connexin43-kinase(s) interactions occurs. ..
  7. Pax6 as a key regulator of lens development
    Ales Cvekl; Fiscal Year: 2013
    ..abstract_text> ..
  8. Lens differentiation and cataract:a role for Wnt-Fz/PCP signaling
    JOHNSTON W MCAVOY; Fiscal Year: 2013
    ....
  9. Lens intercellular communication connexins and cataract
    Thomas W White; Fiscal Year: 2013
    ..They also will broaden the general paradigm of how an integrated system of intercellular communication contributes to the regulation of development in many tissues. ..
  10. Mechanisms of lens growth regulation
    Xiaohua Gong; Fiscal Year: 2013
    ..Anticipated results may be useful for developing a new strategy to inhibit lens size increase, thus delaying or preventing presbyopia and age-related cataract. ..
  11. Epigenetic regulation of lens fiber cell differentiation: The role of DNA methyla
    Michael L Robinson; Fiscal Year: 2013
    ..We will use histological, immunological and high throughput next generation sequencing strategies to comprehensively investigate how DNA methylation influences lens fiber cell differentiation. ..
  12. Role of Aquaporin-0 for cell-to-cell adhesion and lens transparency
    Kulandaiappan Varadaraj; Fiscal Year: 2013
    ..The objectives will be pursued using structure-function approach and performing cytological, biochemical and molecular biological experiments as appropriate to verify the results. ..
  13. Genetic determinants of cataract
    Alan Shiels; Fiscal Year: 2013
    ..abstract_text> ..
  14. IPF Fibroblast Phenotype
    Craig A Henke; Fiscal Year: 2013
    ..A major objective of this Program Project is to inform decisions of the IPF Clinical Network by providing information that can be translated into novel therapeutic strategies for IPF. ..