June 2020
Volume 61, Issue 7
Free
ARVO Annual Meeting Abstract  |   June 2020
Gclc influences eye development: possible link between protein glutathionylation and gene expression in the lens
Author Affiliations & Notes
  • Brian Thompson
    Environmental Health Sciences, Yale University, New Haven, Connecticut, United States
  • Ying Chen
    Environmental Health Sciences, Yale University, New Haven, Connecticut, United States
  • Julien Philippe
    Center for Human Disease Modeling, Duke University Medical Center, North Carolina, United States
  • Nicholas Katsanis
    Northwestern University Feinberg School of Medicine, Chicago, Illinois, United States
    Stanley Manne Research Institute, Chicago, Illinois, United States
  • David Orlicky
    Department of Pathology, University of Colorado, Aurora, Colorado, United States
  • David Thompson
    Department of Clinical Pharmacy, University of Colorado, Colorado, United States
  • Vasilis Vasiliou
    Environmental Health Sciences, Yale University, New Haven, Connecticut, United States
  • Footnotes
    Commercial Relationships   Brian Thompson, None; Ying Chen, None; Julien Philippe, None; Nicholas Katsanis, None; David Orlicky, None; David Thompson, None; Vasilis Vasiliou, None
  • Footnotes
    Support  EY22312-7
Investigative Ophthalmology & Visual Science June 2020, Vol.61, 2868. doi:
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      Brian Thompson, Ying Chen, Julien Philippe, Nicholas Katsanis, David Orlicky, David Thompson, Vasilis Vasiliou; Gclc influences eye development: possible link between protein glutathionylation and gene expression in the lens. Invest. Ophthalmol. Vis. Sci. 2020;61(7):2868.

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      © ARVO (1962-2015); The Authors (2016-present)

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Abstract

Purpose : Glutamate-cysteine ligase catalytic subunit (Gclc) is an essential enzyme in the biosynthesis of glutathione (GSH). We have previously demonstrated that gclc suppression in zebrafish and Gclc deletion from surface ectoderm-derived tissues in the mouse both induce microphthalmia. However, the mechanism by which this induces microphthalmia remains unknown. By impacting cellular redox signaling and the oxidation status of exposed thiols in proteins, decreased levels of GSH (subsequent to ablated Gclc activity) may promote microphthalmia by influencing the proteome or transcriptome of the developing lens.

Methods : Gclc-floxed mice were bred with Le-Cre transgenic (which utilize the Pax6 P0 gene promoter to drive CRE recombinase expression) mice to create KO mice in which Gclc was conditionally deleted from only the surface ectoderm-derived tissues within the developing eye. Gclc-floxed mice serve as the control. Changes in the redox status of the lens proteome was estimated by Western blot analysis of glutathionylated proteins in the lens of postnatal day (P) 21 mice. qRT-PCR was used to determine alterations in lens gene expression in P0 mice.

Results : At P21, KO lens display increased global protein glutathionylation compared with Gclc control (CON) mice. Notably, high molecular weight (>40 kDa) lens proteins were selectively glutathionylated in KO but not control mice. At P0, the KO lens transcriptome revealed marked changes in the expression of stress response genes (i.e., Hmox1, Cdkn1a), Foxe3 (essential lens epithelial transcription factor), and Cryaa (lens molecular chaperone).

Conclusions : Our results provide evidence that suppression of Gclc influences important lens transcription factors and results in the glutathionylation of select lens proteins. Investigations into the role of protein glutathionylation in causing gene expression changes that adversely affect eye development and cause microphthalmia are on-going.

This is a 2020 ARVO Annual Meeting abstract.

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