1. HOXA13 directly regulates EphA6 and EphA7 expression in the genital tubercle vascular endothelia.
- Author
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Shaut CA, Saneyoshi C, Morgan EA, Knosp WM, Sexton DR, and Stadler HS
- Subjects
- Animals, Base Sequence, Binding Sites, Cells, Cultured, Endothelium, Vascular metabolism, Genitalia metabolism, Green Fluorescent Proteins genetics, Green Fluorescent Proteins metabolism, Homeodomain Proteins genetics, Homeodomain Proteins metabolism, Mice, Mice, Mutant Strains, Molecular Sequence Data, Promoter Regions, Genetic, Receptor, EphA6 metabolism, Receptor, EphA7 metabolism, Recombinant Fusion Proteins genetics, Recombinant Fusion Proteins metabolism, Sequence Homology, Nucleic Acid, Transfection, Endothelium, Vascular embryology, Gene Expression Regulation, Developmental, Genitalia blood supply, Genitalia embryology, Homeodomain Proteins physiology, Receptor, EphA6 genetics, Receptor, EphA7 genetics
- Abstract
Hypospadias, a common defect affecting the growth and closure of the external genitalia, is often accompanied by gross enlargements of the genital tubercle (GT) vasculature. Because Hoxa13 homozygous mutant mice also exhibit hypospadias and GT vessel expansion, we examined whether genes playing a role in angiogenesis exhibit reduced expression in the GT. From this analysis, reductions in EphA6 and EphA7 were detected. Characterization of EphA6 and EphA7 expression in the GT confirmed colocalization with HOXA13 in the GT vascular endothelia. Analysis of the EphA6 and EphA7 promoter regions revealed a series of highly conserved cis-regulatory elements bound by HOXA13 with high affinity. GT chromatin immunoprecipitation confirmed that HOXA13 binds these gene-regulatory elements in vivo. In vitro, HOXA13 activates gene expression through the EphA6 and EphA7 gene-regulatory elements. Together these findings indicate that HOXA13 directly regulates EphA6 and EphA7 in the developing GT and identifies the GT vascular endothelia as a novel site for HOXA13-dependent expression of EphA6 and EphA7.
- Published
- 2007
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