title: Dysfunction of the stress-responsive FOXC1 transcription factor contributes to the earlier-onset glaucoma observed in Axenfeld-Rieger syndrome patients.
abstract: Mutations in the Forkhead Box C1 (FOXC1) transcription factor gene are associated with Axenfeld-Rieger syndrome (ARS), a developmental disorder affecting structures in the anterior segment of the eye. Approximately 75% of ARS patients with FOXC1 mutations develop earlier-onset glaucoma. Constant exposure of the trabecular meshwork (TM), located in the anterior segment of the eye, to oxidative stress is predicted to be a risk factor for developing glaucoma. Stress-induced death of TM cells results in dysfunction of the TM, leading to elevated intraocular pressure, which is a major risk factor for developing glaucoma. FOXC1 is predicted to maintain homeostasis in TM cells by regulating genes that are important for stress response. In this study, we show that a member of the heat-shock 70 family of proteins, HSPA6, is a target gene of FOXC1. HSPA6 protein, which is only induced under severe oxidative stress conditions, has a protective function in human trabecular meshwork (HTM) cells. We also show that FOXC1 is anti-apoptotic as knocking down FOXC1 significantly decreases HTM cell viability. In addition, we show that FOXC1 itself responds to stress as exposure of cells to H2O2-induced oxidative stress reduces FOXC1 levels and activity. Conditions that decrease FOXC1 function, such as exposure of cells to oxidative stress and FOXC1 ARS mutations, compromise the ability of TM cells to effectively respond to environmental stresses. Dysfunction of FOXC1 contributes to the death of TM cells, an important step in the development of glaucoma.
authors.affiliation: Department of Medical Genetics, University of Alberta, Alberta T6G 2H7, Canada.
authors.forename: Y A
authors.initials: YA
authors.lastname: Ito
authors.affiliation: Department of Biochemistry, University of Alberta, Alberta T6G 2H7, Canada.
authors.forename: I S
authors.initials: IS
authors.lastname: Goping
authors.affiliation: 1] Department of Medical Genetics, University of Alberta, Alberta T6G 2H7, Canada [2] Department of Surgery, University of Alberta, Alberta T6G 2H7, Canada.
authors.forename: F
authors.initials: F
authors.lastname: Berry
authors.affiliation: 1] Department of Medical Genetics, University of Alberta, Alberta T6G 2H7, Canada [2] Department of Ophthalmology, University of Alberta, Alberta T6G 2H7, Canada.
authors.forename: M A
authors.initials: MA
authors.lastname: Walter
mesh_terms: D000869:Anterior Eye Segment / Q000002:abnormalities* / Q000378:metabolism / Q000473:pathology; D017209:Apoptosis; D002470:Cell Survival; D002478:Cells, Cultured; D005124:Eye Abnormalities / Q000150:complications* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015785:Eye Diseases, Hereditary; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D020022:Genetic Predisposition to Disease; D005901:Glaucoma / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D006801:Humans; D009154:Mutation; D016877:Oxidants / Q000494:pharmacology; D018384:Oxidative Stress / Q000187:drug effects; D010641:Phenotype; D034622:RNA Interference; D014129:Trabecular Meshwork / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D014162:Transfection
chemical_list: C112743:FOXC1 protein, human; D051858:Forkhead Transcription Factors; D018840:HSP70 Heat-Shock Proteins; C544598:HSPA6 protein, human; D016877:Oxidants