Somatic TERT promoter mutations are an early, highly prevalent genetic event in UBC and are not associated with TERT mRNA levels or disease outcomes. A SNaPshot assay in urine may help to detect UBC recurrences.

The primary lung bud originates from the foregut and develops into the bronchial tree by repetitive branching and outgrowing of the airway. The Sry related HMG box protein Sox2 is expressed in a cyclic manner during initiation and branching morphogenesis of the lung. It is highly expressed in non-branching regions and absent from branching regions, suggesting that downregulation of Sox2 is mandatory for airway epithelium to respond to branch inducing signals. Therefore, we developed transgenic mice that express a doxycycline inducible Sox2 in the airway epithelium. Continuous expression of Sox2 hampers the branching process resulting in a severe reduction of the number of airways. In addition, the bronchioli transiently go over into enlarged, alveolar-like airspaces, a pathology described as bronchiolization of alveoli. Furthermore, a substantial increase was observed of cGRP positive neuroendocrine cells and Delta Np63 isoform expressing (pre-) basal cells, which are both committed precursor-like cells. Thus, Sox2 prevents airways from branching and prematurely drives cells into committed progenitors, apparently rendering these committed progenitors unresponsive to branch inducing signals. However, Sox2 overexpression does not lead to a complete abrogation of the epithelial differentiation program.

Abstract-The Fibulins are a 6-member protein family hypothesized to function as intermolecular bridges that stabilize the organization of extracellular matrix structures. Here, we show that reduced expression of Fibulin-4 leads to aneurysm formation, dissection of the aortic wall and cardiac abnormalities. Fibulin-4 knockdown mice with a hypomorphic expression allele arose from targeted disruption of the adjacent Mus81 endonuclease gene. Mice homozygous for the Fibulin-4 reduced expression allele (Fibulin-4 R/R ) show dilatation of the ascending aorta and a tortuous and stiffened aorta, resulting from disorganized elastic fiber networks. They display thickened aortic valvular leaflets that are associated with aortic valve stenosis and insufficiency. Strikingly, already a modest reduction in expression of Fibulin-4 in the heterozygous ϩ/R mice occasionally resulted in small aneurysm formation. To get insight into the underlying molecular pathways involved in aneurysm formation and response to aortic failure, we determined the aorta transcriptome of ϩ/R and Fibulin-4 R/R animals and identified distinct and overlapping biological processes that were significantly overrepresented including cytoskeleton organization, cell adhesion, apoptosis and several novel gene targets. Transcriptome and protein expression analysis implicated perturbation of TGF-␤ signaling in the pathogenesis of aneurysm in fibulin-4 deficient mice. Our results show that the dosage of a single gene can determine the severity of aneurysm formation and imply that disturbed TGF-␤ signaling underlies multiple aneurysm phenotypes. (Circ Res. 2007;100:738-746.)Key Words: aneurysm Ⅲ aortic valve Ⅲ mouse model E xtracellular elastic fibers supply structure and mechanical elasticity to organs such as large arteries, lungs and skin. 1 Elastic fibers are assembled through polymerization of tropoelastin monomers and loss of elastin is associated with aneurysmal degeneration of the aorta. 2 The 6-member protein family of Fibulins, which are prominently expressed in blood vessels are hypothesized to function as intermolecular bridges that stabilize the organization of extracellular structures such as elastic fibers and basement membranes. 3 Fibulin-4 is found in the medial layers of arteries and heart valves. 4 Whereas complete Fibulin-4 knockout mice have recently been generated 5 and showed embryonic lethality (E12.5), we generated a Fibulin-4 allele with reduced expression by transcriptional interference through placement of a TKneo targeting construct in a downstream gene (Mus81). Mus81 knockout mice have been generated previously. 6,7 In the targeting strategy of Dendouga et al, exons 9 to 12 were replaced by a PGKneo marker flanked by loxP sites and subsequently the marker was excised using Cre-recombinase expressing mice. Mus81 knockout mice from which the selectable marker was removed were born at expected Mendelian frequencies and were indistinguishable from WT littermates in terms of development, growth, immune function and fertility. 6 To examine ...