Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth

Seungwoon Seo, Hardeep P. Singh, Pedro M. Lacal, Amy Sasman, Anees Fatima, Ting Liu, Kathryn M. Schultz, Douglas W. Losordo, Ordan J. Lehmann, Tsutomu Kume

Research output: Contribution to journalArticle

55 Citations (Scopus)

Abstract

Normal vision requires the precise control of vascular growth to maintain corneal transparency. Here we provide evidence for a unique mechanism by which the Forkhead box transcription factor FoxC1 regulates corneal vascular development. Murine Foxc1 is essential for development of the ocular anterior segment, and in humans, mutations have been identified in Axenfeld-Rieger syndrome, a disorder characterized by anterior segment dysgenesis. We show that FOXC1 mutations also lead to corneal angiogenesis, and that mice homozygous for either a global (Foxc1 -/-) or neural crest (NC)-specific (NC-Foxc1 -/-) null mutation display excessive growth of corneal blood and lymphatic vessels. This is associated with disorganization of the extracellular matrix and increased expression of multiple matrix metalloproteinases. Heterozygous mutants (Foxc1 +/- and NC-Foxc1 +/-) exhibit milder phenotypes, such as disrupted limbal vasculature. Moreover, environmental exposure to corneal injury significantly increases growth of both blood and lymphatic vessels in both Foxc1 +/- and NC-Foxc1 +/-mice compared with controls. Notably, this amplification of the angiogenic response is abolished by inhibition of VEGF receptor 2. Collectively, these findings identify a role for FoxC1 in inhibiting corneal angiogenesis, thereby maintaining corneal transparency by regulating VEGF signaling.

Original languageEnglish
Pages (from-to)2015-2020
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume109
Issue number6
DOIs
Publication statusPublished - Feb 7 2012

Fingerprint

Forkhead Transcription Factors
Neural Crest
Blood Vessels
Corneal Neovascularization
Lymphatic Vessels
Growth
Mutation
Vascular Endothelial Growth Factor Receptor
Environmental Exposure
Matrix Metalloproteinases
Vascular Endothelial Growth Factor A
Extracellular Matrix
Phenotype

Keywords

  • Avascularity
  • Soluble form of VEGF receptor 1
  • VEGF bioavailablility

ASJC Scopus subject areas

  • General

Cite this

Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth. / Seo, Seungwoon; Singh, Hardeep P.; Lacal, Pedro M.; Sasman, Amy; Fatima, Anees; Liu, Ting; Schultz, Kathryn M.; Losordo, Douglas W.; Lehmann, Ordan J.; Kume, Tsutomu.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 109, No. 6, 07.02.2012, p. 2015-2020.

Research output: Contribution to journalArticle

Seo, Seungwoon ; Singh, Hardeep P. ; Lacal, Pedro M. ; Sasman, Amy ; Fatima, Anees ; Liu, Ting ; Schultz, Kathryn M. ; Losordo, Douglas W. ; Lehmann, Ordan J. ; Kume, Tsutomu. / Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth. In: Proceedings of the National Academy of Sciences of the United States of America. 2012 ; Vol. 109, No. 6. pp. 2015-2020.
@article{c8f99ba1d7694800bc06a039f5cdbab5,
title = "Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth",
abstract = "Normal vision requires the precise control of vascular growth to maintain corneal transparency. Here we provide evidence for a unique mechanism by which the Forkhead box transcription factor FoxC1 regulates corneal vascular development. Murine Foxc1 is essential for development of the ocular anterior segment, and in humans, mutations have been identified in Axenfeld-Rieger syndrome, a disorder characterized by anterior segment dysgenesis. We show that FOXC1 mutations also lead to corneal angiogenesis, and that mice homozygous for either a global (Foxc1 -/-) or neural crest (NC)-specific (NC-Foxc1 -/-) null mutation display excessive growth of corneal blood and lymphatic vessels. This is associated with disorganization of the extracellular matrix and increased expression of multiple matrix metalloproteinases. Heterozygous mutants (Foxc1 +/- and NC-Foxc1 +/-) exhibit milder phenotypes, such as disrupted limbal vasculature. Moreover, environmental exposure to corneal injury significantly increases growth of both blood and lymphatic vessels in both Foxc1 +/- and NC-Foxc1 +/-mice compared with controls. Notably, this amplification of the angiogenic response is abolished by inhibition of VEGF receptor 2. Collectively, these findings identify a role for FoxC1 in inhibiting corneal angiogenesis, thereby maintaining corneal transparency by regulating VEGF signaling.",
keywords = "Avascularity, Soluble form of VEGF receptor 1, VEGF bioavailablility",
author = "Seungwoon Seo and Singh, {Hardeep P.} and Lacal, {Pedro M.} and Amy Sasman and Anees Fatima and Ting Liu and Schultz, {Kathryn M.} and Losordo, {Douglas W.} and Lehmann, {Ordan J.} and Tsutomu Kume",
year = "2012",
month = "2",
day = "7",
doi = "10.1073/pnas.1109540109",
language = "English",
volume = "109",
pages = "2015--2020",
journal = "Proceedings of the National Academy of Sciences of the United States of America",
issn = "0027-8424",
number = "6",

}

TY - JOUR

T1 - Forkhead box transcription factor FoxC1 preserves corneal transparency by regulating vascular growth

AU - Seo, Seungwoon

AU - Singh, Hardeep P.

AU - Lacal, Pedro M.

AU - Sasman, Amy

AU - Fatima, Anees

AU - Liu, Ting

AU - Schultz, Kathryn M.

AU - Losordo, Douglas W.

AU - Lehmann, Ordan J.

AU - Kume, Tsutomu

PY - 2012/2/7

Y1 - 2012/2/7

N2 - Normal vision requires the precise control of vascular growth to maintain corneal transparency. Here we provide evidence for a unique mechanism by which the Forkhead box transcription factor FoxC1 regulates corneal vascular development. Murine Foxc1 is essential for development of the ocular anterior segment, and in humans, mutations have been identified in Axenfeld-Rieger syndrome, a disorder characterized by anterior segment dysgenesis. We show that FOXC1 mutations also lead to corneal angiogenesis, and that mice homozygous for either a global (Foxc1 -/-) or neural crest (NC)-specific (NC-Foxc1 -/-) null mutation display excessive growth of corneal blood and lymphatic vessels. This is associated with disorganization of the extracellular matrix and increased expression of multiple matrix metalloproteinases. Heterozygous mutants (Foxc1 +/- and NC-Foxc1 +/-) exhibit milder phenotypes, such as disrupted limbal vasculature. Moreover, environmental exposure to corneal injury significantly increases growth of both blood and lymphatic vessels in both Foxc1 +/- and NC-Foxc1 +/-mice compared with controls. Notably, this amplification of the angiogenic response is abolished by inhibition of VEGF receptor 2. Collectively, these findings identify a role for FoxC1 in inhibiting corneal angiogenesis, thereby maintaining corneal transparency by regulating VEGF signaling.

AB - Normal vision requires the precise control of vascular growth to maintain corneal transparency. Here we provide evidence for a unique mechanism by which the Forkhead box transcription factor FoxC1 regulates corneal vascular development. Murine Foxc1 is essential for development of the ocular anterior segment, and in humans, mutations have been identified in Axenfeld-Rieger syndrome, a disorder characterized by anterior segment dysgenesis. We show that FOXC1 mutations also lead to corneal angiogenesis, and that mice homozygous for either a global (Foxc1 -/-) or neural crest (NC)-specific (NC-Foxc1 -/-) null mutation display excessive growth of corneal blood and lymphatic vessels. This is associated with disorganization of the extracellular matrix and increased expression of multiple matrix metalloproteinases. Heterozygous mutants (Foxc1 +/- and NC-Foxc1 +/-) exhibit milder phenotypes, such as disrupted limbal vasculature. Moreover, environmental exposure to corneal injury significantly increases growth of both blood and lymphatic vessels in both Foxc1 +/- and NC-Foxc1 +/-mice compared with controls. Notably, this amplification of the angiogenic response is abolished by inhibition of VEGF receptor 2. Collectively, these findings identify a role for FoxC1 in inhibiting corneal angiogenesis, thereby maintaining corneal transparency by regulating VEGF signaling.

KW - Avascularity

KW - Soluble form of VEGF receptor 1

KW - VEGF bioavailablility

UR - http://www.scopus.com/inward/record.url?scp=84857126252&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84857126252&partnerID=8YFLogxK

U2 - 10.1073/pnas.1109540109

DO - 10.1073/pnas.1109540109

M3 - Article

VL - 109

SP - 2015

EP - 2020

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

SN - 0027-8424

IS - 6

ER -