HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: iovs.09-3447v1 50/11/5026    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Skarie, J. M. Articles by Link, B. A. Search for Related Content PubMed PubMed Citation Articles by Skarie, J. M. Articles by Link, B. A.

FoxC1 Is Essential for Vascular Basement Membrane Integrity and Hyaloid Vessel Morphogenesis

From the Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, Wisconsin.

Corresponding author: Brian A. Link, Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, 8701 Watertown Plank Road, BSB 405, Milwaukee, WI 53226; blink{at}mcw.edu.

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 -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.