Human Molecular Genetics Advance Access originally published online on December 16, 2008
Human Molecular Genetics 2009 18(5):966-977; doi:10.1093/hmg/ddn424
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Altered visual function and interneuron survival in Atrx knockout mice: inference for the human syndrome
1 Regenerative Medicine 2 Vision Programs, Ottawa Health Research Institute, Ottawa, Ontario, Canada K1H 8L6 3 Department of Medicine, Biochemistry, Microbiology, Immunology 4 Department of Opthalmology, University of Ottawa, Ontario, Canada K1H 8C8 5 University of Ottawa Eye Institute, University of Ottawa, Ottawa, Canada K1H 8L6 6 Medical Research Council Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, UK
* To whom correspondence should be addressed at: Ottawa Health Research Institute, 501 Smyth Road, Ottawa, Ontario, Canada, K1H 8L6. Tel: +1 6137378989; Fax: +1 6137378803; Email: dpicketts{at}ohri.ca
Received October 24, 2008; Revised November 28, 2008; Accepted December 9, 2008
ATRX is an SWI/SNF-like chromatin remodeling protein that is mutated in several X-linked mental retardation syndromes, including the ATR-X syndrome. In mice, Atrx expression is widespread and attempts to understand its function in brain development are hampered by the lethality associated with ubiquitous or forebrain-restricted ablation of this gene. One way to circumvent this problem is to study its function in a region of the brain that is dispensable for long-term survival of the organism. The retina is a well-characterized tractable model of CNS development and in our review of 202 ATR-X syndrome patients, we found ocular defects present in 
25% of the cases, suggesting that studying Atrx in this tissue will provide insight into function. We report that Atrx is expressed in the neuroprogenitor pool in embryonic retina and in all cell types of the mature retina with the exception of rod photoreceptors. Conditional inactivation of Atrx in the retina during embryogenesis ultimately results in a loss of only two types of neurons, amacrine and horizontal cells. We show that this defect does not arise from a failure to specify these cells but rather a defect in interneuron differentiation and survival post-natally. The timing of cell loss is concomitant with light-dependent changes in synaptic organization in the retina and with a change in Atrx subnuclear localization within these interneurons. Moreover, these interneuron defects are associated with functional deficits as demonstrated by reduced b-wave amplitudes upon electroretinogram analysis. These results implicate a role for Atrx in interneuron survival and differentiation.
Present address: Department of Biochemistry and Department of Paediatrics, University of Western Ontario; Child Health Research Institute and Lawson Health Research Institute, London, Ontario, Canada. 
These authors made equal contributions.