Human Molecular Genetics Advance Access originally published online on November 9, 2007
Human Molecular Genetics 2008 17(4):490-505; doi:10.1093/hmg/ddm326
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FOXC1 is required for cell viability and resistance to oxidative stress in the eye through the transcriptional regulation of FOXO1A
1 Department of Medical Genetics, University of Alberta, Edmonton, AB, Canada 2 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA 3 McGill University and Genome Quebec Innovation Centre, Montreal, PQ, Canada 4 Laboratory of Ocular Genetics and Genomics, Molecular Endocrinology and Oncology Research Center, Laval University Hospital (CHUL) Research Center, Québec City,PQ, Canada
* To whom correspondence should be addressed at: Department of Medical Genetics, University of Alberta, 832 Medical Sciences Building, Edmonton, AB, Canada, T6G 2H7. Tel: +1 7804923028; Fax: +1 7804926934; Email: fberry{at}ualberta.ca
Received October 12, 2007; Revised October 12, 2007; Accepted November 6, 2007
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.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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