In Drosophila the decision processes between the neural and epidermal fate for equipotent ectodermal cells depend on the activity of proneural genes. Members of the Drosophila Iroquois-Complex (Iro-C) positively regulate the activity of certain proneural AS-C genes during the formation of external sensory organs. We have identified and characterized three mouse Iroquois-related genes: Irx1, -2 and -3, which have a homeodomain very similar to that of the Drosophila Iro-C genes. The sequence similarity implies that these three genes represent a separate homeobox family. All three genes are expressed with distinct spatio/temporal patterns during early mouse embryogenesis. These patterns implicate them in a number of embryonic developmental processes: the A/P and D/V patterning of specific regions of the central nervous system (CNS), and regionalization of the otic vesicle, branchial epithelium and limbs.
We describe the sequence and expression pattern of Sp5, a novel member of the vertebrate Sp1 transcription factor gene family which consists of at least five members. This gene family is characterized by a highly conserved domain which is formed by three Zn fingers, which bind to the GC box or the GT/CACC box in the promoter of many genes. These boxes are important cis-acting elements required for the expression of the respective genes. In vitro experiments indicate that the Sp1 transcription factors act by influencing the methylation state of the DNA, or by direct interactions with other promoter specific transcription factors. Despite intensive research, the results from in vivo experiments, including targeted gene inactivation, have been difficult to explain. This may be due to possible redundancies and interferences with other transcription factors of this gene family. Here, we report the isolation of the mouse Sp5 gene, a novel Sp1 homolog. Its sequence indicates that Sp5 is a possible link between Sp1 and the closely related BTEB/KLF gene family. We provide detailed information of its highly dynamic expression pattern during mouse embryogenesis in the developing brain, the spinal cord, the trigeminal ganglia, the somites and additional sites outside the nervous system starting from embryonic day 7.25 (E7.25) up to E10.5.
Major determinants of the bioavailability of drugs are the degree of intestinal absorption and the hepatic first-pass effect. Drugs need to overcome several membrane barriers before reaching the systemic circulation, each of which expresses an array of specialized transport proteins for drug uptake or efflux. The P-glycoprotein MDR1 (multidrug resistance gene product, ABCB1) is expressed at the apical surface of enterocytes, where it mediates the efflux of xenobiotics into the intestinal lumen before these can access the portal circulation. Increased expression of MDR1 reduces the bioavailability of MDR1 substrates such as digoxin, cyclosporin, and taxol. Numerous xenobiotics can induce the MDR1 gene through activation of the nuclear pregnane X receptor (PXR). This explains the risk for drug interactions that is inherent to pharmacotherapy with PXR ligands such as rifampin, phenobarbital, statins, and St. John's wort. Other PXR-regulated genes include cytochrome P450 3A4, the digoxin and bile salt transporter Oatp2 (organic anion transporting polypeptide 2, Slc01a4) of the basolateral hepatocyte membrane, and the xenobiotic efflux pump Mrp2 (multidrug resistance associated protein 2, Abcc2) of the canalicular hepatocyte membrane. A second orphan nuclear receptor that is activated by xenobiotics is the constitutive androstane receptor (CAR), which induces Mrp2 and Mrp3 (Abcc3). The PXR and CAR are thus important "xenosensors" that mediate drug-induced activation of the detoxifying transport and enzyme systems in liver and intestine.
Irx1 and Irx2 are members of the murine Iroquois homeobox (Irx) gene family. In this study, we describe the dynamic expression pattern of these genes during limb development with a focus on digit formation. We further present a comparative expression analysis with Gli genes (Gli1, Gli2, Gli3). Gli1, Gli2, and Gli3 were suggested for candidate regulators of the Irx genes. The expression was studied between E11.5 and E14.5 when the digits are being formed. Irx1 and Irx2 reproduce the developmental program of the digits in time and space and the Irx1 provides an early and excellent marker for this process. Our analysis also indicates that the expression of Irx1, Gli1 and Irx2, Gli2 are relative to each other. In contrast, Gli3 exhibits a different expression pattern.
We describe a comparative lung expression analysis of the murine Irx1 and Irx2 genes. At embryonic day 8.5 (E8.5), the Irx1 and Irx2 expression starts in the foregut region, where the laryngo-tracheal groove will form. The expression is prominent in the lung epithelium during glandular development. It declines at the end of the canalicular phase. We further compare the Irx1 and Irx2 expression domains to Gli1, 2, 3 and Mash1. Their homologues in Drosophila melanogaster are known as regulative partners of the iroquois complex. The Irx and Gli genes are coexpressed in the developing lungs at the same time. Their transcripts are not localised in the same cells but adjacent to each other in either mesenchymal or epithelial structures. It is thought that the lung development is regulated by the mesenchymal/epithelial interactions.
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