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The Winged Helix Transcription Factor HFH-4 is Expressed during Choroid Plexus Epithelial Development in the Mouse Embryo
Lorena Lim, Heping Zhou and Robert H. Costa
Proceedings of the National Academy of Sciences of the United States of America
Vol. 94, No. 7 (Apr. 1, 1997), pp. 3094-3099
Published by: National Academy of Sciences
Stable URL: http://www.jstor.org/stable/41781
Page Count: 6
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Mammalian hepatocyte nuclear factor-3 (HNF-3) and the Drosophila homeotic gene fork head proteins are prototypes of an extensive family of cell-specific transcription factors that share homology in the winged helix DNA-binding domain. One of these mammalian family members, HNF-3/fork head homolog-4 (HFH-4), was isolated by PCR amplification of rodent brain cDNA and exhibits abundant expression in the adult bronchiolar epithelium. In this study, we performed in situ hybridization of stage-specific mouse embryos and report on a novel expression pattern of the HFH-4 gene in both the presumptive and differentiated choroid plexus epithelium, which is responsible for the synthesis and secretion of cerebrospinal fluid (CSF) proteins. We also showed that HFH-4 is a potent transcriptional activator in cotransfection assays and defined several protein sequences important for HFH-4 transcriptional activity. We used in vitro DNA-binding site selection with recombinant HFH-4 protein and determined that the HFH-4 protein recognizes the DNA consensus sequences HWDTGTTTGTTTA or KTTTGTTGTTKTW (where H is not G, W is A or T, D is not C, and K is G or T). We used this HFH-4 consensus to identify potential HFH-4 target genes in the choroid plexus epithelium and demonstrated that these promoter sequences bind to recombinant HFH-4 protein in electrophoretic mobility shift assays. Recombinant HFH-4 formed specific protein-DNA complexes with the promoter regions of the human prothrombin, beta amyloid precursor protein, α 1-antichymotrypsin, cystic fibrosis transmembrane conductance regulator and rodent α 2-macroglobulin, growth hormone receptors, and insulin-like growth factor II genes. Furthermore, we identified putative HFH-4 target genes in the bronchiolar epithelium including the clara cell secretory protein gene and the HNF-3α gene, a winged helix family member involved in the transcriptional regulation of genes in the bronchiolar epithelium. In support of these binding studies, cotransfection assays show that HFH-4 potentiates expression of the HNF-3α and clara cell secretory protein promoter regions.
Proceedings of the National Academy of Sciences of the United States of America © 1997 National Academy of Sciences