PT  - JOURNAL ARTICLE
AU  - Brian Thompson
AU  - Ying Chen
AU  - Julien Philippe
AU  - David Anderson
AU  - Jaya Prakash Golla
AU  - Emily Davidson
AU  - Nicholas Apostolopoulos
AU  - Kevin Schey
AU  - Nicholas Katsanis
AU  - David J. Orlicky
AU  - David Thompson
AU  - Vasilis Vasiliou
TI  - <em>Gclc</em> deletion in surface-ectoderm tissues induces microphthalmia
AID  - 10.1101/700591
DP  - 2019 Jan 01
TA  - bioRxiv
PG  - 700591
4099  - http://biorxiv.org/content/early/2019/07/24/700591.short
4100  - http://biorxiv.org/content/early/2019/07/24/700591.full
AB  - Glutamate cysteine ligase catalytic subunit (Gclc) is the catalytic subunit for the glutamate-cysteine ligase (Gcl) enzyme. Gcl catalyzes the rate limiting step in glutathione (GSH) synthesis. Gclc is highly expressed in the developing eye. To define the regulatory role of Gclc in eye development, we developed a novel, Le-Cre transgene-driven, Gclc knockout mouse model. Gclcf/f/Le-CreTg/− mice present with deformation of the retina, cornea, iris, and lens, consistent with a microphthalmia phenotype. Controlling for the microphthalmia phenotype of Gclcwt/wt/Le-CreTg/− mice revealed that Gclcf/f/Le-CreTg/− mice have a more severe microphthalmia phenotype. Thus, the loss of Gclc expression exacerbates the microphthalmia phenotype in Le-Cre mice. Gclcf/f/Le-CreTg/− eyes present with reduced retinal and lens epithelium proliferation and increased lens cell death. Imaging mass spectrometry of ocular tissues revealed changes in the intensity and distribution of several lipid species and proteins in the retina and corneas of Gclcf/f/Le-CreTg/− eyes. Lastly, using splice-blocking morpholinos and CRISPR/Cas9, we created two gclc knockdown zebrafish models, both of which display a microphthalmia phenotype. Combined, the mouse and zebrafish results indicate that, in chordates, Gclc has a conserved role in regulating eye development. In summary, these novel animal models are useful tools for elucidating the mechanisms involved in microphthalmia development.