Retinal interneuron survival requires non-cell-autonomous Atrx activity.
ATRX is a chromatin remodeling protein that is mutated in several intellectual disability disorders including alpha-thalassemia/mental retardation, X-linked (ATR-X) syndrome. We previously reported the prevalence of ophthalmological defects in ATR-X syndrome patients, and accordingly we find morphological and functional visual abnormalities in a mouse model harboring a mutation occurring in ATR-X patients. The visual system abnormalities observed in these mice parallels the Atrx-null retinal phenotype characterized by interneuron defects and selective loss of amacrine and horizontal cells. The mechanisms that underlie selective neuronal vulnerability and neurodegeneration in the central nervous system upon Atrx mutation or deletion are unknown. To interrogate the cellular specificity of Atrx for its retinal neuroprotective functions, we employed a combination of temporal and lineage-restricted conditional ablation strategies to generate five different conditional knockout mouse models, and subsequently identified a non-cell-autonomous requirement for Atrx in bipolar cells for inhibitory interneuron survival in the retina. Atrx-deficient retinal bipolar cells exhibit functional, structural and molecular alterations consistent with impairments in neuronal activity and connectivity. Gene expression changes in the Atrx-null retina indicate defective synaptic structure and neuronal circuitry, suggest excitotoxic mechanisms of neurodegeneration, and demonstrate that common targets of ATRX in the forebrain and retina may contribute to similar neuropathological processes underlying cognitive impairment and visual dysfunction in ATR-X syndrome.
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Pamela S
PS
Lagali
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Chantal F
CF
Medina
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Brandon Y H
BY
Zhao
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Keqin
K
Yan
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.
Adam N
AN
Baker
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.|Department of Ophthalmology, University of Ottawa, Ottawa, ON K1H 8M5, Canada,|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada,
Stuart G
SG
Coupland
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.|Department of Ophthalmology, University of Ottawa, Ottawa, ON K1H 8M5, Canada,|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada,
Catherine
C
Tsilfidis
Vision Research Division, Krembil Research Institute, Toronto, Ontario, Canada M5T 2S8,|Department of Ophthalmology and Vision Sciences, University of Toronto, Toronto, ON M5T 3A9, Canada
Valerie A
VA
Wallace
Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, ON K1H 8L6, Canada.|Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON K1H 8M5, Canada,|Department of Biochemistry, Microbiology, and Immunology, University of Ottawa, Ottawa, ON K1H 8M5, Canada
David J
DJ
Picketts
D000818:Animals; D002843:Chromatin; D004195:Disease Models, Animal; D007395:Interneurons / Q000378:metabolism; D008297:Male; D038901:X-Linked Intellectual Disability / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D009154:Mutation; D009474:Neurons / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics; D012160:Retina / Q000378:metabolism; D051245:Retinal Bipolar Cells / Q000378:metabolism; D000075924:X-linked Nuclear Protein / Q000235:genetics* / Q000378:metabolism; D017085:alpha-Thalassemia / Q000235:genetics* / Q000378:metabolism
D002843:Chromatin; D009687:Nuclear Proteins; C490462:Atrx protein, mouse; D000075924:X-linked Nuclear Protein