Purchase this article with an account.
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)
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.
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.
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.
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