title: FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A.
abstract: Mutations in the human FOXC1 transcription factor gene underlie Axenfeld-Rieger (AR) syndrome, a disorder characterized by anterior segment malformations in the eye and glaucoma. Through the use of an inducible FOXC1 protein, along with an intermediate protein synthesis blocker, we have determined direct targets of FOXC1 transcriptional regulation. FOXC1 regulates the expression of FOXO1A and binds to a conserved element in the FOXO1A promoter in vivo. The zebrafish foxO1a orthologs exhibit a robust expression pattern in the periocular mesenchyme. Furthermore, FOXO1A expression is reduced in cultured human trabecular meshwork (TM) cells and in the zebrafish developing eye when FOXC1 expression is knocked down by siRNAs and morpholino antisense oliognucleotides, respectively. We also demonstrate that reduced FOXC1 expression increases cell death in cultured TM cells in response to oxidative stress, and increases cell death in the developing zebrafish eye. These studies have uncovered a novel role for FOXC1 as an essential mediator of cellular homeostasis in the eye and indicate that a decreased resistance to oxidative stress may underlie AR-glaucoma pathogenesis. Given that FOXO1A influences cellular homeostasis when positively or negatively regulated; the dysregulation of FOXO1A activities in the eye through FOXC1 loss of function mutations and FOXC1 gene duplications provides an explanation into how seemingly similar human disorders can arise from both increases and decreases in FOXC1 gene dose.
authors.affiliation: Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada. fberry@ualberta.ca
authors.forename: Fred B
authors.initials: FB
authors.lastname: Berry
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Skarie
authors.forename: Farideh
authors.initials: F
authors.lastname: Mirzayans
authors.forename: Yannick
authors.initials: Y
authors.lastname: Fortin
authors.forename: Thomas J
authors.initials: TJ
authors.lastname: Hudson
authors.forename: Vincent
authors.initials: V
authors.lastname: Raymond
authors.forename: Brian A
authors.initials: BA
authors.lastname: Link
authors.forename: Michael A
authors.initials: MA
authors.lastname: Walter
mesh_terms: D000818:Animals; D000867:Anterior Chamber / Q000002:abnormalities; D001665:Binding Sites / Q000235:genetics; D002470:Cell Survival / Q000235:genetics / Q000502:physiology; D002478:Cells, Cultured; D005123:Eye / Q000196:embryology / Q000378:metabolism*; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000378:metabolism*; D018628:Gene Dosage; D005901:Glaucoma / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D009154:Mutation; D018384:Oxidative Stress; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D014129:Trabecular Meshwork / Q000166:cytology / Q000378:metabolism; D014158:Transcription, Genetic; D015027:Zebrafish / Q000196:embryology / Q000235:genetics / Q000378:metabolism; D029961:Zebrafish Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C112743:FOXC1 protein, human; C085126:FOXO1 protein, human; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D029961:Zebrafish Proteins