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Wilms' tumor (WT) is one of the most common solid tumors of childhood. The genetics of this disorder is complex and few studies have suggested allelic loss of chromosome 22 as a frequent aberration. To assess tumor- and possible germline-specific regions affected with gene copy number variations on this chromosome, we applied a high-resolution genomic clone-based chromosome 22 array to a series of 28 WT samples and the paired blood-derived DNA of the patients. The group of tumors was enriched for cases with metastases, relapse or fatal outcome, criteria that were expected to yield a higher number of alterations on chromosome 22. Overall, the array-based form of comparative genomic hybridization (array-CGH) analysis revealed genomic changes in 53% (15 out of 28) of cases. We identified hemizygous deletion of the whole arm of 22q in 3 tumors (11%). Furthermore, a complex amplifier genotype was detected in 8 samples, presenting regions of gain along the chromosome, which defined 7 distinct minimal overlapping segments. The distribution of aberrations in 4 additional cases displaying regional genomic imbalances delimited 2 tumor suppressor/oncogene candidate loci, 1 in the proximal and the other in the terminal part of 22q. Analysis of these regions revealed the presence of several candidate genes that may play a role in the development of WT. These findings demonstrate the power of array-CGH in the determination of DNA copy number alterations and further strength the notion that WT-associated genes exist on this chromosome., (Copyright (c) 2006 Wiley-Liss, Inc.)

The dachsous (ds), fat (ft), and four-jointed (fj) genes have been identified in Drosophila as part of a signaling pathway that regulates planar cell polarity (PCP). A homologous PCP signaling pathway has also been identified in vertebrates, but nothing is known thus far about the conservation of Ds/Ft/Fj signaling. Here we analyzed and compared for the first time the expression patterns of all ds, ft and fj homologs in the mouse. During embryogenesis, expression analysis was performed by RNA in situ hybridization and in adult organs by real time PCR. As in Drosophila, we detected a complementary expression of fjx1 and dchs1 in organs like kidney, lung, and intestine. The ubiquitous expression of ft in several tissues in Drosophila appears to be split into an epithelial expression of fat1/fat3 and a mesenchymal expression of fat-j. These data are compatible with a conservation and sub-functionalization of the Drosophila Ds, Fj, and Fat signaling in higher vertebrates., (Developmental Dynamics 234:747-755, 2005. (c) 2005 Wiley-Liss, Inc.)

Hairy-related transcription factor (HRT/Hey) genes encode a novel subfamily of basic helix-loop-helix (bHLH) transcription factors related to the Drosophila hairy and Enhancer-of-split (E(spl)) and the mammalian HES proteins that function as downstream mediators of Notch signaling. Using the yeast two-hybrid approach, a previously uncharacterized protein was identified in Xenopus that interacts with XHRT1 (originally referred to as bc8), one member of the HRT/Hey subclass. This protein is evolutionarily conserved in chordates. It binds to sequences adjacent to the bHLH domain of XHRT1 known as the Orange domain and has been named bc8 Orange interacting protein (BOIP). BOIP shows a rather uniform subcellular localization and is recruited to the nucleus upon binding to XHRT1. In Xenopus, XBOIP mRNA is detected by RNase protection analysis throughout embryogenesis. In the adult, the strongest expression is detected in testis. In the mouse, high levels of BOIP mRNA are also found in adult testis. No expression is detected in the embryo and in any of the other adult organs tested. In situ hybridization revealed that BOIP transcripts were detected almost exclusively in round spermatids and that this expression overlaps with that of Hey1 (HRT1), which is expressed throughout spermatogenesis. In view of the importance of the Orange domain for HRT/Hey function, the newly identified BOIP proteins may serve as regulators specifically of HRT1/Hey1 activity., (Copyright 2003 Wiley-Liss, Inc.)

Hey genes encode a small family of basic helix-loop-helix (bHLH) transcription factors that are related to the Drosophila hairy and Enhancer-of-split genes. They belong to the still-limited number of direct targets of the Notch signaling pathway and are thus candidate molecules to effect critical developmental decisions like lateral inhibition, boundary formation, and inductive processes in numerous tissues. Human inherited mutations such as cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukencephalopathy and Alagille syndrome, as well as several mouse models, have highlighted the role of Notch signals in cardiovascular development and maintenance. Functional analyses in both mouse and zebrafish now have shown that Hey genes appear to be the most prominent transmitters for such signals to shape the cardiovascular system during development and perhaps also in later life.

A substantial percentage of human pregnancies are lost as spontaneous abortions after implantation. This is often caused by an inadequately developed placenta. Proper development of the placental vascular system is essential to nutrient and gas exchange between mother and developing embryo. Here we show that alpha(2)-adrenoceptors, which are activated by adrenaline and noradrenaline, are important regulators of placental structure and function. Mice with deletions in the genes encoding alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors died between embryonic days 9.5 and 11.5 from a severe defect in yolk-sac and placenta development. In wildtype placentae, alpha(2)-adrenoceptors are abundantly expressed in giant cells, which secrete angiogenic factors to initiate development of the placental vascular labyrinth. In placentae deficient in alpha(2A)-, alpha(2B)- and alpha(2C)-adrenoceptors, the density of fetal blood vessels in the labyrinth was markedly lower than normal, leading to death of the embryos as a result of reduced oxygen and nutrient supply. Basal phosphorylation of the extracellular signal regulated kinases ERK1 and ERK2 was also lower than normal, suggesting that activation of the mitogen-activated protein kinase (MAP kinase) pathway by alpha(2)-adrenoceptors is required for placenta and yolk-sac vascular development. Thus, alpha(2)-adrenoceptors are essential at the placental interface between mother and embryo to establish the circulatory system of the placenta and thus maintain pregnancy.