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FoxC1 is essential for vascular basement membrane integrity and hyaloid vessel morphogenesis. Invest Ophthalmol Vis Sci 2009 Nov;50(11):5026-34

Date

05/22/2009

Pubmed ID

19458328

Pubmed Central ID

PMC3651675

DOI

10.1167/iovs.09-3447

Scopus ID

2-s2.0-78649436084   38 Citations

Abstract

PURPOSE: 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.

Author List

Skarie JM, Link BA

Author

Brian A. Link PhD Professor in the Cell Biology, Neurobiology and Anatomy department at Medical College of Wisconsin




MESH terms used to index this publication - Major topics in bold

Animals
Basement Membrane
Biomarkers
Endothelium, Vascular
Eye
Fluorescein Angiography
Fluorescent Antibody Technique, Indirect
Forkhead Transcription Factors
Gene Expression
Gene Knockout Techniques
Gene Silencing
In Situ Hybridization
Laminin
Lens, Crystalline
Microscopy, Confocal
Microscopy, Electron, Transmission
Morphogenesis
Ophthalmic Artery
Zebrafish
Zebrafish Proteins
jenkins-FCD Prod-486 e3098984f26de787f5ecab75090d0a28e7f4f7c0