Human Molecular Genetics Advance Access originally published online on September 25, 2006
Human Molecular Genetics 2006 15(21):3229-3240; doi:10.1093/hmg/ddl400
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FGF19 is a target for FOXC1 regulation in ciliary body-derived cells
1 Department of Medical Genetics, 2 Department of Ophthalmology and 3 Department of Medical Genetics, 839 MSB, University of Alberta, Edmonton, Alberta, Canada T6G 2H7 and 4 Department of Cell Biology Neurobiology and Anatomy, Medical College of Wisconsin, Milwaukee, WI, USA
* To whom correspondence should be addressed. Tel: +1 7804929044; Fax: +1 7804926934; Email: mwalter{at}ualberta.ca
Received July 24, 2006; Accepted September 18, 2006
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.
The authors wish it to be known that, in their opinion, the first three authors should be regarded as joint First Authors.
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