FGF19 is a target for FOXC1 regulation in ciliary body-derived cells.
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.
Tamimi
Yahya
Y
Department of Medical Genetics, University of Alberta, Edmonton, Alberta, Canada.
Skarie
Jonathan M
JM
Footz
Tim
T
Berry
Fred B
FB
Link
Brian A
BA
Walter
Michael A
MA
D000818:Animals; D001483:Base Sequence; D002460:Cell Line; D047369:Chromatin Immunoprecipitation / Q000379:methods; D002924:Ciliary Body / Q000166:cytology; D005346:Fibroblast Growth Factors / Q000235:genetics*; D051858:Forkhead Transcription Factors / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D005901:Glaucoma / Q000235:genetics; D006801:Humans; D020935:MAP Kinase Signaling System; D008969:Molecular Sequence Data; D014162:Transfection; D015027:Zebrafish / Q000196:embryology / Q000235:genetics*; D029961:Zebrafish Proteins / Q000235:genetics*
C117476:FGF19 protein, human; C112743:FOXC1 protein, human; C507702:Fgf19 protein, zebrafish; D051858:Forkhead Transcription Factors; C426857:Foxc1a protein, zebrafish; C426858:Foxc1b protein, zebrafish; D029961:Zebrafish Proteins; D005346:Fibroblast Growth Factors