September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Investigating Mechanisms of Visual Dysfunction in Mouse Models of ATR-X Syndrome
Author Affiliations & Notes
  • Pamela S Lagali
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada
  • Brandon Y H Zhao
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Keqin Yan
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
  • Adam N Baker
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada
  • Stuart G Coupland
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada
  • Catherine Tsilfidis
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    University of Ottawa Eye Institute, Ottawa, Ontario, Canada
  • David J Picketts
    Regenerative Medicine, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
    Department of Biochemistry, Microbiology, and Immunolog, University of Ottawa, Ottawa, Ontario, Canada
  • Footnotes
    Commercial Relationships   Pamela Lagali, None; Brandon Zhao, None; Keqin Yan, None; Adam Baker, None; Stuart Coupland, None; Catherine Tsilfidis, None; David Picketts, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 610. doi:
  • Views
  • Share
  • Tools
    • Alerts
      ×
      This feature is available to Subscribers Only
      Sign In or Create an Account ×
    • Get Citation

      Pamela S Lagali, Brandon Y H Zhao, Keqin Yan, Adam N Baker, Stuart G Coupland, Catherine Tsilfidis, David J Picketts; Investigating Mechanisms of Visual Dysfunction in Mouse Models of ATR-X Syndrome. Invest. Ophthalmol. Vis. Sci. 2016;57(12):610.

      Download citation file:


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

      ×
  • Supplements
Abstract

Purpose : ATR-X syndrome is characterized by severe intellectual disability accompanied by a spectrum of defects affecting multiple organ systems, including ophthalmic abnormalities. The precise role of the Atrx gene in causing pleiotropic dysfunction is unknown. We use tissue-specific Atrx knockout models and a transgenic mouse harbouring a clinically relevant mutation to investigate mechanisms of disease pathogenesis. Here we assess the effect of retinal Atrx deficiency to gain insight into visual defects and neuronal dysfunction in ATR-X syndrome.

Methods : A Cre recombinase-dependent conditional knockout (cKO) strategy using the retinal Chx10-GFP/Cre-IRES-AP driver line and Atrx-floxed mice generated retina-specific Atrx cKO mice. AtrxΔE2 mice mimic the C109T (R37X) protein-truncating mutation identified in ATR-X patients. Protein levels and distribution in mouse retinal tissues were assessed by immunodetection techniques. Differential gene expression was analyzed using DNA microarrays, bioinformatics, and qRT-PCR. Electroretinography was performed to measure scotopic a-wave and b-wave amplitudes, implicit times, and oscillatory potentials.

Results : AtrxΔE2 mice have reduced Atrx protein levels in the retina similar to mutant brain tissue and patient-derived lymphoblasts. Selective loss of amacrine and horizontal cells is observed for AtrxΔE2 retinas and is paralleled in the Atrx cKO mice. Functional deficits in both mutant mouse models include reduced scotopic b-wave amplitudes and diminished oscillatory potentials. Bipolar cell markers are misexpressed in the mutant retinas and protein distribution indicates morphological abnormalities of multiple bipolar cell subtypes. Transcriptional profiling of the Atrx cKO retinas reveals downregulation of genes involved in neurotransmitter metabolism and neuronal communication, and reflects an excitotoxic environment. Furthermore, synaptic proteins are similarly dysregulated in Atrx-null retina and forebrain tissues.

Conclusions : Atrx deficiency compromises the survival of retinal inhibitory interneurons and is associated with defects in retinal bipolar cells. Gene expression changes indicate defective synaptic structure and neuronal circuitry, suggest excitotoxic mechanisms of neurodegeneration, and demonstrate that common targets of Atrx in the retina and brain may contribute to similar neuropathology underlying visual dysfunction and cognitive impairment in ATR-X syndrome.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

×
×

This PDF is available to Subscribers Only

Sign in or purchase a subscription to access this content. ×

You must be signed into an individual account to use this feature.

×