Lens intercellular communication connexins and cataract

Summary

Principal Investigator: Thomas W White
Abstract: DESCRIPTION (provided by applicant): Connexins are the subunit proteins of gap junctions, which allow the exchange of ions, second messengers and small metabolites between adjacent cells through intercellular channels. Gap junctional communication is important in the development and maintenance of lens, as mutations in lens connexin genes cause cataract and developmental defects in humans and mice. Signal transduction pathways have also been shown to play critical roles in lens development and homeostasis, and mutations in signaling genes like phosphatase and tensin homolog (PTEN) cause complex human syndromic disorders that include cataract. Although great progress has been made, there are still substantial gaps in our knowledge about potential cooperation between these two different intercellular communication systems. In this proposal, our objective is to further define how gap junctional communication interacts with other intercellular signal transduction pathways in the lens. We propose first to examine the consequences of PI3K deficiency by generating and characterizing conditional knockout mice lacking the p110a and p110b catalytic subunits of PI3K in the lens. Second, we will make conditional knockout mice lacking PTEN in the lens, and examine their phenotype. Finally, we will investigate interactions between lens gap junctional coupling and the PI3K/Akt and PTEN signaling pathways in postnatal growth and homeostasis by using pharmacological blockers, electrophysiological measurements and biochemical assays in vitro. We will also cross PI3K and PTEN conditional knockout animals with connexin knockout mice to confirm interactions in vivo. These studies will provide insights into how gap junctional coupling and signal transduction pathways synergistically interact to regulate lens growth and homeostasis by combining in vitro pharmacological and electrophysiological assays with in vivo animal models. They also will broaden the general paradigm of how an integrated system of intercellular communication contributes to the regulation of development in many tissues.
Funding Period: 2000-07-01 - 2016-11-30
more information: NIH RePORT

Top Publications

  1. ncbi Knock-in of alpha3 connexin prevents severe cataracts caused by an alpha8 point mutation
    Chun hong Xia
    School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA, USA
    J Cell Sci 119:2138-44. 2006
  2. ncbi Connexin-26 mutations in deafness and skin disease
    Jack R Lee
    Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York 11794 8661, USA
    Expert Rev Mol Med 11:e35. 2009
  3. ncbi Lens gap junctions in growth, differentiation, and homeostasis
    Richard T Mathias
    Department of Physiology and Biophysics, SUNY at Stony Brook, Stony Brook, New York 11794 8661, USA
    Physiol Rev 90:179-206. 2010
  4. pmc Zebrafish cx30.3: identification and characterization of a gap junction gene highly expressed in the skin
    Liang Tao
    Department of Biological Sciences, University of Manitoba, Winnipeg, Canada
    Dev Dyn 239:2627-36. 2010
  5. pmc Properties of connexin 46 hemichannels in dissociated lens fiber cells
    Lisa Ebihara
    Departments of Physiology and Biophysics, Rosalind Franklin School of Medicine and Science, North Chicago, Illinois 60064, USA
    Invest Ophthalmol Vis Sci 52:882-9. 2011
  6. pmc Lens intracellular hydrostatic pressure is generated by the circulation of sodium and modulated by gap junction coupling
    Junyuan Gao
    Department of Physiology and Biophysics, SUNY at Stony Brook, NY 11794, USA
    J Gen Physiol 137:507-20. 2011
  7. pmc The effect of size and species on lens intracellular hydrostatic pressure
    Junyuan Gao
    Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794 8661, USA
    Invest Ophthalmol Vis Sci 54:183-92. 2013
  8. pmc Cataracts and microphthalmia caused by a Gja8 mutation in extracellular loop 2
    Chun hong Xia
    School of Optometry and Vision Science Program, University of California, Berkeley, California, United States of America
    PLoS ONE 7:e52894. 2012
  9. pmc Functional effects of Cx50 mutations associated with congenital cataracts
    Clio Rubinos
    Department of Biological and Vision Sciences and the Graduate Center for Vision Research, State University of New York College of Optometry, New York, New York and
    Am J Physiol Cell Physiol 306:C212-20. 2014
  10. pmc The effects of age on lens transport
    Junyuan Gao
    Department of Physiology and Biophysics, SUNY at Stony Brook, Stony Brook, New York
    Invest Ophthalmol Vis Sci 54:7174-87. 2013

Detail Information

Publications26

  1. ncbi Knock-in of alpha3 connexin prevents severe cataracts caused by an alpha8 point mutation
    Chun hong Xia
    School of Optometry and Vision Science Program, University of California at Berkeley, Berkeley, CA, USA
    J Cell Sci 119:2138-44. 2006
    ..Thus, knocked-in alpha3 connexin and mutant alpha8-G22R connexin probably form heteromeric gap junction channels that influence lens homeostasis and lens transparency...
  2. ncbi Connexin-26 mutations in deafness and skin disease
    Jack R Lee
    Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York 11794 8661, USA
    Expert Rev Mol Med 11:e35. 2009
    ..Here, we summarise the functional consequences and clinical phenotypes resulting from Cx26 mutations that cause deafness and skin disease...
  3. ncbi Lens gap junctions in growth, differentiation, and homeostasis
    Richard T Mathias
    Department of Physiology and Biophysics, SUNY at Stony Brook, Stony Brook, New York 11794 8661, USA
    Physiol Rev 90:179-206. 2010
    ....
  4. pmc Zebrafish cx30.3: identification and characterization of a gap junction gene highly expressed in the skin
    Liang Tao
    Department of Biological Sciences, University of Manitoba, Winnipeg, Canada
    Dev Dyn 239:2627-36. 2010
    ..Thus, zebrafish could potentially serve as an excellent model to study disorders of the skin and deafness that result from human connexin mutations...
  5. pmc Properties of connexin 46 hemichannels in dissociated lens fiber cells
    Lisa Ebihara
    Departments of Physiology and Biophysics, Rosalind Franklin School of Medicine and Science, North Chicago, Illinois 60064, USA
    Invest Ophthalmol Vis Sci 52:882-9. 2011
    ..To characterize the properties of connexin 46 hemichannels in differentiating fiber cells isolated from mouse lenses...
  6. pmc Lens intracellular hydrostatic pressure is generated by the circulation of sodium and modulated by gap junction coupling
    Junyuan Gao
    Department of Physiology and Biophysics, SUNY at Stony Brook, NY 11794, USA
    J Gen Physiol 137:507-20. 2011
    ....
  7. pmc The effect of size and species on lens intracellular hydrostatic pressure
    Junyuan Gao
    Department of Physiology and Biophysics, State University of New York at Stony Brook, Stony Brook, New York 11794 8661, USA
    Invest Ophthalmol Vis Sci 54:183-92. 2013
    ..Model calculations predicted that in larger lenses, all else equal, pressure should increase as the lens radius squared. To test this prediction, lenses of different radii from different species were studied...
  8. pmc Cataracts and microphthalmia caused by a Gja8 mutation in extracellular loop 2
    Chun hong Xia
    School of Optometry and Vision Science Program, University of California, Berkeley, California, United States of America
    PLoS ONE 7:e52894. 2012
    ..This work provides molecular insights to understand the cataract and microphthalmia/microcornea phenotype caused by Gja8 mutations in mice and humans...
  9. pmc Functional effects of Cx50 mutations associated with congenital cataracts
    Clio Rubinos
    Department of Biological and Vision Sciences and the Graduate Center for Vision Research, State University of New York College of Optometry, New York, New York and
    Am J Physiol Cell Physiol 306:C212-20. 2014
    ..These results suggest that unique interactions between mutant and wild-type lens connexins might underlie the development of various cataract phenotypes in humans. ..
  10. pmc The effects of age on lens transport
    Junyuan Gao
    Department of Physiology and Biophysics, SUNY at Stony Brook, Stony Brook, New York
    Invest Ophthalmol Vis Sci 54:7174-87. 2013
    ..Age-related nuclear cataracts involve denaturation and aggregation of intracellular proteins. We have documented age-dependent changes in membrane transport in the mouse lens to see what might initiate changes in the intracellular milieu...
  11. pmc The cataract causing Cx50-S50P mutant inhibits Cx43 and intercellular communication in the lens epithelium
    Adam M DeRosa
    Department of Physiology and Biophysics, State University of New York, T5 147, Basic Science Tower, Stony Brook, NY 11794 8661, USA
    Exp Cell Res 315:1063-75. 2009
    ..These data suggest that dominant inhibition of Cx43 mediated epithelial cell coupling may play a role in the lens pathophysiology caused by the Cx50-S50P mutation...
  12. pmc Interaction between Connexin50 and mitogen-activated protein kinase signaling in lens homeostasis
    Teresa I Shakespeare
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, NY 11794 8661, USA
    Mol Biol Cell 20:2582-92. 2009
    ..These results indicate that MAPK signaling specifically modulates coupling mediated by Cx50 and that gap junctional communication and signal transduction pathways may interact in osmotic regulation during postnatal fiber development...
  13. pmc Functional characterization of a naturally occurring Cx50 truncation
    Adam M DeRosa
    Graduate Program in Genetics, State University of New York, Stony Brook, NY 11794 8661, USA
    Invest Ophthalmol Vis Sci 47:4474-81. 2006
    ..This study evaluates the functional consequences of this endogenous truncation by characterizing the properties of a C-terminal truncated Cx50 protein...
  14. ncbi Mefloquine effects on the lens suggest cooperative gating of gap junction channels
    Francisco J Martinez-Wittinghan
    Department of Physiology and Biophysics, State University of New York, Stony Brook, NY 11794 8661, USA
    J Membr Biol 211:163-71. 2006
    ..These results suggest the two types of channels interact and gate cooperatively...
  15. ncbi Aberrant hemichannel properties of Cx26 mutations causing skin disease and deafness
    Dwan A Gerido
    Dept of Physiology and Biophysics, State University of New York, T5 147, Basic Science Tower, Stony Brook, NY 11794 8661, USA
    Am J Physiol Cell Physiol 293:C337-45. 2007
    ..These data suggest that mutant hemichannels may act on cellular homeostasis in a manner that can be detrimental to the tissues in which they are expressed...
  16. pmc Zebrafish short fin mutations in connexin43 lead to aberrant gap junctional intercellular communication
    Angela D Hoptak-Solga
    Lehigh University, Department of Biological Sciences, Iacocca B 217, Bethlehem, PA 18015, USA
    FEBS Lett 581:3297-302. 2007
    ..Therefore, measurable differences in Cx43 function may be correlated with the severity of defects in bone length...
  17. ncbi Human connexin26 and connexin30 form functional heteromeric and heterotypic channels
    Sabrina W Yum
    Section of Neurology, St Christopher s Hospital For Children, Erie Ave at Front St, Philadelphia, PA 19134, USA
    Am J Physiol Cell Physiol 293:C1032-48. 2007
    ..These results indicate that Cx26 and Cx30 form functional heteromeric and heterotypic channels, whose biophysical properties and permeabilities are different from their homotypic counterparts...
  18. ncbi Gap junctions: basic structure and function
    Gulistan Mese
    1Program in Genetics, Stony Brook University, Stony Brook, New York, USA
    J Invest Dermatol 127:2516-24. 2007
    ..Here, we discuss the basic structure of gap junction channels and the function of connexin genes that have been associated with human disorders to explore the physiology of intercellular communication in skin...
  19. ncbi The cataract-inducing S50P mutation in Cx50 dominantly alters the channel gating of wild-type lens connexins
    Adam M DeRosa
    Department of Physiology and Biophysics and the Graduate Program in Genetics, State University of New York, Stony Brook, NY 11794, USA
    J Cell Sci 120:4107-16. 2007
    ..Additionally, mixed channels displayed significantly altered gating properties, a phenomenon that may contribute to the cataract that is associated with this mutation...
  20. ncbi Optimal lens epithelial cell proliferation is dependent on the connexin isoform providing gap junctional coupling
    Thomas W White
    Department of Physiology and Biophysics, Stony Brook University, Stony Brook, New York, USA
    Invest Ophthalmol Vis Sci 48:5630-7. 2007
    ..To determine which connexins functionally contribute to epithelial cell coupling and proliferation, junctional coupling from epithelial cells of wild-type and knockin mice was examined...
  21. pmc Connexin26 deafness associated mutations show altered permeability to large cationic molecules
    Gulistan Mese
    Graduate Program in Genetics, State University of New York, Stony Brook, New York 11794 8661, USA
    Am J Physiol Cell Physiol 295:C966-74. 2008
    ..Altered permeability of Cx26 to large cationic molecules suggests an essential role for biochemical coupling in cochlear homeostasis...
  22. ncbi Connexin mutations causing skin disease and deafness increase hemichannel activity and cell death when expressed in Xenopus oocytes
    Jack R Lee
    Department of Physiology and Biophysics, Stony Brook University Medical Center, Stony Brook, New York 11794 8661, USA
    J Invest Dermatol 129:870-8. 2009
    ..This set of data confirms that aberrant hemichannel activity is a common feature of Cx26 mutations associated with KID syndrome, and this may contribute to a loss of cell viability and tissue integrity...
  23. ncbi The effects of GPX-1 knockout on membrane transport and intracellular homeostasis in the lens
    Huan Wang
    Department of Physiology and Biophysics, SUNY at Stony Brook, Stony Brook, NY 11794 8661, USA
    J Membr Biol 227:25-37. 2009
    ..This reduction affected the lens normal circulation by causing [Na+]i and [Ca2+]i to increase, which could increase cataract susceptibility in GPX-1 KO lenses...