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Human Molecular Genetics Advance Access published online on September 25, 2006
Human Molecular Genetics, doi:10.1093/hmg/ddl400
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© The Author 2006. Published by Oxford University Press. All rights reserved
Received July 24, 2006
Revised September 18, 2006
Accepted September 18, 2006

Article

FGF19 is a target for FOXC1 regulation in ciliary body derived cells

Yahya Tamimi 1, Jonathan M. Skarie 2, Tim Footz 1, Fred B. Berry 3, Brian A. Link 2, and Michael A. Walter 4 *

1 Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada
2 Department of Cell Biology, Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
3 Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada
4 Department of Medical Genetics, 839 MSB, University of Alberta, Edmonton, Alberta, Canada T6G 2H7; Department of Ophthalmology, University of Alberta, Edmonton, Alberta, Canada

* To whom correspondence should be addressed.
Michael A. Walter, E-mail: mwalter{at}ualberta.ca


  Abstract

The forkhead C1 (FOXC1) transcription factor is involved in the development and regulation of several organs, including the eye, where FOXC1 alterations cause iris, trabecular meshwork and corneal anomalies. Using nickel agarose chromatin enrichment with human anterior segment cells we previously identified the fibroblast growth factor 19 (FGF19) locus as a gene potentially regulated by FOXC1. Here we demonstrate that FGF19 is a direct target of FOXC1 in the eye. FOXC1 positively regulates FGF19 expression in corneal and periocular mesenchymal cells in cell culture and in zebrafish embryos. Through the FGFR4 tyrosine kinase, FGF19 promotes MAPK phosphorylation in the developing and mature cornea. During development, loss of either FOXC1 or FGF19 results in complementary, but distinct anterior segment dysgeneses. This study reveals an important role for FOXC1 in the direct regulation of the FGF19-FGFR4-MAPK pathway to promote both the development and maintenance of anterior segment structures within the eye.


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