Peroxisome proliferator activated receptors, transcription factors belonging to the nuclear re ceptor superfamily, upregulate megalin expression, but it is not yet known whether these factors influence cubilin expression. Furthermore, expression of megalin is regulated by histone KPT-330 msds acetylation and methylation and DNA methylation, but it is not yet known whether cubilin Inhibitors,Modulators,Libraries is regulated epigenetically in a similar manner. The availability of a mouse carrying a knockin of an EGFP cassette into the cubilin gene has enabled precise histological analysis of cubilin expression. While evaluating cubilin EGFP expression in renal tissue of mice heterozygous for the knockin allele, we observed a striking difference in the distribution of EGFP immunore activity versus cubilin immunoreactivity.
Although both were detected at sites that matched cubilin distribution in wildtype animals, the Inhibitors,Modulators,Libraries cellular distributions in heterozygous mice were largely exclusive such that cells appeared to ex press predominantly either EGFP or cubilin. This led us to postulate that cubilin might undergo an allelic inactivation that silenced or strongly diminished expression of either the maternal or paternal allele. This phenomenon, called monoallelic expression, can occur through chromo somal inactivation, autosomal gene imprinting or random gene inactivation. Monoallelic expression of a variety of autosomal genes have been described, including p120 catenin, certain cy tokines, olfactory receptors and antigen receptors.
Here we explored the possibility that cubilin, an autosomal gene, is regulated through epi genetic mechanisms and whether such processes might have consequences on cubilin function and on the expres sion of its partners, amnionless and megalin. Results Monoallelic expression of cubilin Inhibitors,Modulators,Libraries in the renal proximal tubules Kidney sections from wildtype mice and mice heterozy Inhibitors,Modulators,Libraries gous for Cubn exon 1 6 deletion with an EGFP cassette insertion were immunolabeled with antibodies to cubilin and EGFP. In kidneys from wildtype mice, all proximal tubules displayed prominent and relatively uniform brush border immunolabeling with anti cubilin IgG. By contrast, the kidneys of Cubn del exon 1 6.EGFP mice showed strong immunolabeling in the brush border regions of only a subset of proximal tubules.
Evaluation of EGFP immunolabeling in kidney sections from these mice revealed a similar discontinuous distribution, with some cells showing high levels of anti Inhibitors,Modulators,Libraries EGFP immuno fluorescence while adjacent cells had only weak fluores cence. However, strikingly, the epithelial Rucaparib structure cells that had strong EGFP immunofluorescence displayed little or no cubilin immunolabeling. Conversely, the proximal tubules that showed relatively low EGFP immunofluorescence displayed pronounced cubilin immunolabeling. Similar observations were made in the kidneys of female Cubn mice.