title: Loss of Otx2 in the adult retina disrupts retinal pigment epithelium function, causing photoreceptor degeneration.
abstract: Photoreceptors are specialized neurons of the retina that receive nursing from the adjacent retinal pigment epithelium (RPE). Frequent in the elderly, photoreceptor loss can originate from primary dysfunction of either cell type. Despite intense interest in the etiology of these diseases, early molecular actors of late-onset photoreceptor degeneration remain elusive, mostly because of the lack of dedicated models. Conditional Otx2 ablation in the adult mouse retina elicits photoreceptor degeneration, providing a new model of late-onset neuronal disease. Here, we use this model to identify the earliest events after Otx2 ablation. Electroretinography and gene expression analyses suggest a nonautonomous, RPE-dependent origin for photoreceptor degeneration. This is confirmed by RPE-specific ablation of Otx2, which results in similar photoreceptor degeneration. In contrast, constitutive Otx2 expression in RPE cells prevents degeneration of photoreceptors in Otx2-ablated retinas. We use chromatin immunoprecipitation followed by massive sequencing (ChIP-seq) analysis to identify the molecular network controlled in vivo by Otx2 in RPE cells. We uncover four RPE-specific functions coordinated by Otx2 that underpin the cognate photoreceptor degeneration. Many direct Otx2 target genes are associated with human retinopathies, emphasizing the significance of the model. Importantly, we report a secondary genetic response after Otx2 ablation, which largely precedes apoptosis of photoreceptors, involving inflammation and stress genes. These findings thus provide novel general markers for clinical detection and prevention of neuronal cell death.
authors.affiliation: Institut de Biologie Valrose, University of Nice Sophia Antipolis, UFR Sciences, Nice F-06108, France.
authors.forename: Michael
authors.initials: M
authors.lastname: Housset
authors.forename: Alexander
authors.initials: A
authors.lastname: Samuel
authors.forename: Mohamed
authors.initials: M
authors.lastname: Ettaiche
authors.forename: Alexis
authors.initials: A
authors.lastname: Bemelmans
authors.forename: Francis
authors.initials: F
authors.lastname: Béby
authors.forename: Nathalie
authors.initials: N
authors.lastname: Billon
authors.forename: Thomas
authors.initials: T
authors.lastname: Lamonerie
mesh_terms: D000367:Age Factors; D000818:Animals; D001253:Astrocytes / Q000502:physiology; D047369:Chromatin Immunoprecipitation; D004195:Disease Models, Animal; D004596:Electroretinography; D005260:Female; D020869:Gene Expression Profiling; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics*; D005822:Genetic Vectors / Q000502:physiology; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016086:Lentivirus / Q000235:genetics; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008954:Models, Biological; D020411:Oligonucleotide Array Sequence Analysis; D051857:Otx Transcription Factors / Q000172:deficiency* / Q000235:genetics; D010786:Photoreceptor Cells / Q000378:metabolism / Q000473:pathology*; D011485:Protein Binding / Q000187:drug effects / Q000235:genetics; D012333:RNA, Messenger; D012160:Retina / Q000473:pathology*; D012162:Retinal Degeneration / Q000235:genetics / Q000473:pathology; D055213:Retinal Pigment Epithelium / Q000473:pathology / Q000503:physiopathology*
chemical_list: D051857:Otx Transcription Factors; C497660:Otx2 protein, mouse; D012333:RNA, Messenger; D049452:Green Fluorescent Proteins