title: FoxC1 is essential for vascular basement membrane integrity and hyaloid vessel morphogenesis.
abstract: OBJECTIVE
  Alterations in FOXC1 dosage lead to a spectrum of highly penetrant, ocular anterior segment dysgenesis phenotypes. The most serious outcome is the development of glaucoma, which occurs in 50% to 75% of patients. Therefore, the need to identify specific pathways and genes that interact with FOXC1 to promote glaucoma is great. In this study, the authors investigated the loss of foxC1 in the zebrafish to characterize phenotypes and gene interactions that may impact glaucoma pathogenesis.
  
  
  METHODS
  Morpholino knockdown in zebrafish, RNA and protein marker analyses, transgenic reporter lines, and angiography, along with histology and transmission electron microscopy, were used to study foxC1 function and gene interactions.
  
  
  RESULTS
  Zebrafish foxC1 genes were expressed dynamically in the developing vasculature and periocular mesenchyme during development. Multiple ocular and vascular defects were found after the knockdown of foxC1. Defects in the hyaloid vasculature, arteriovenous malformations, and coarctation of the aorta were observed with maximal depletion of foxC1. Partial loss of foxC1 resulted in CNS and ocular hemorrhages, defects in intersegmental vessel patterning, and increased vascular permeability. To investigate the basis for these disruptions, the ultrastructure of foxC1-depleted hyaloid vascular cells was studied. These experiments, along with laminin-111 immunoreactivity, revealed disruptions in basement membrane integrity. Finally, codepletion of laminin alpha-1 and foxC1 uncovered a genetic interaction between these genes during development.
  
  
  CONCLUSIONS
  Genetic interactions between FOXC1 and basement membrane components influence vascular stability and may impact glaucoma development and increase stroke risk in FOXC1 patients.
authors.affiliation: Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin 53226, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Skarie
authors.forename: Brian A
authors.initials: BA
authors.lastname: Link
mesh_terms: D000818:Animals; D001485:Basement Membrane / Q000098:blood supply* / Q000378:metabolism / Q000473:pathology; D015415:Biomarkers / Q000378:metabolism; D004730:Endothelium, Vascular / Q000378:metabolism* / Q000473:pathology; D005123:Eye / Q000196:embryology; D005451:Fluorescein Angiography; D019084:Fluorescent Antibody Technique, Indirect; D051858:Forkhead Transcription Factors / Q000502:physiology*; D015870:Gene Expression; D055786:Gene Knockout Techniques; D020868:Gene Silencing; D017403:In Situ Hybridization; D007797:Laminin / Q000378:metabolism; D007908:Lens, Crystalline / Q000098:blood supply; D018613:Microscopy, Confocal; D046529:Microscopy, Electron, Transmission; D009024:Morphogenesis / Q000502:physiology*; D009880:Ophthalmic Artery / Q000196:embryology* / Q000378:metabolism / Q000473:pathology; D015027:Zebrafish / Q000196:embryology*; D029961:Zebrafish Proteins / Q000378:metabolism / Q000502:physiology*
chemical_list: D015415:Biomarkers; D051858:Forkhead Transcription Factors; C426857:Foxc1a protein, zebrafish; C426858:Foxc1b protein, zebrafish; D007797:Laminin; D029961:Zebrafish Proteins; C510925:laminin alpha1, zebrafish