Casein Kinase 1: A Wnt'er of Disconnect

AbstractPhosphorylation of β-catenin, a central downstream component of the Wnt pathway, by glycogen synthase kinase 3 is essential for its targeted degradation by the proteosome. New studies show that casein kinase 1 primes β-catenin for subsequent phophorylation by glycogen synthase kinase 3

Formation of the blood–brain barrier: Wnt signaling seals the deal

Capillaries in the brain are especially selective in determining which blood-borne components gain access to neurons. The structural elements of this blood–brain barrier (BBB) reside at the tight junction, an intercellular protein complex that welds together adjacent endothelial cell membranes in the microvasculature. In this issue, Liebner et al. (Liebner, S., M. Corada, T. Bangsow, J. Babbage, A. Taddei, C.J. Czupalla, M. Reis, A. Felici, H. Wolburg, M. Fruttiger, et al. 2008. J. Cell Biol. 183: 409–417) report that Wnt signaling plays an active role in the development of the BBB by regulating expression of key protein constituents of the tight junction. Such mechanistic insight has implications for a variety of neuropathological states in which the BBB is breached

Magnetic inflation and stellar mass. III. revised parameters for the component stars of NSVS 07394765

We perform a new analysis of the M-dwarf–M-dwarf eclipsing binary system NSVS 07394765 in order to investigate the reported hyper-inflated radius of one of the component stars. Our analysis is based on archival photometry from the Wide Angle Search for Planets, new photometry from the 32 cm Command Module Observatory telescope in Arizona and the 70 cm telescope at Thacher Observatory in California, and new high-resolution infrared spectra obtained with the Immersion Grating Infrared Spectrograph on the Discovery Channel Telescope. The masses and radii we measure for each component star disagree with previously reported measurements. We show that both stars are early M-type main-sequence stars without evidence for youth or hyper-inflation ( = - ☉ M M + 1 0.661 0.036 0.008 , = - ☉ M M + 2 0.608 0.028 0.003 , = - ☉ + R1 0.599 0.019 R 0.032 , = - ☉ + R2 0.625 0.027 R 0.012 ), and we update the orbital period and eclipse ephemerides for the system. We suggest that the likely cause of the initial hyper-inflated result is the use of moderate-resolution spectroscopy for precise radial velocity measurements.Published versio

AXIN2 -associated autosomal dominant ectodermal dysplasia and neoplastic syndrome

We describe a family with a novel, inherited AXIN2 mutation (c.1989G>A) segregating in an autosomal dominant pattern with oligodontia and variable other findings including colonic polyposis, gastric polyps, a mild ectodermal dysplasia phenotype with sparse hair and eyebrows, and early onset colorectal and breast cancers. This novel mutation predicts p.Trp663X, which is a truncated protein that is missing the last three exons, including the DIX (Disheveled and AXIN interacting) domain. This nonsense mutation is predicted to destroy the inhibitory action of AXIN2 on WNT signaling. Previous authors have described an unrelated family with autosomal dominant oligodontia and a variable colorectal phenotype segregating with a nonsense mutation of AXIN2 , as well as a frameshift AXIN2 mutation in an unrelated individual with oligodontia. Our report provides additional evidence supporting an autosomal dominant AXIN2 -associated ectodermal dysplasia and neoplastic syndrome. © 2011 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/83469/1/33927_ftp.pd

The APC network regulates the removal of mutated cells from colonic crypts

Self-renewal is essential for multicellular organisms but carries the risk of somatic mutations that can lead to cancer, which is particularly critical for rapidly renewing tissues in a highly mutagenic environment such as the intestinal epithelium. Using computational modeling and in vivo experimentation, we have analyzed how adenomatous polyposis coli (APC) mutations and β-catenin aberrations affect the maintenance of mutant cells in colonic crypts. The increasing abundance of APC along the crypt axis forms a gradient of cellular adhesion that causes more proliferative cells to accelerate their movement toward the top of the crypt, where they are shed into the lumen. Thus, the normal crypt can efficiently eliminate β-catenin mutant cells, whereas APC mutations favor retention. Together, the molecular design of the APC/β-catenin signaling network integrates cell proliferation and migration dynamics to translate intracellular signal processing and protein gradients along the crypt into intercellular interactions and whole-crypt physiological or pathological behavior

The Robustness of Pathway Analysis in Identifying Potential Drug Targets in Non-Small Cell Lung Carcinoma

The identification of genes responsible for causing cancers from gene expression data has had varied success. Often the genes identified depend on the methods used for detecting expression patterns, or on the ways that the data had been normalized and filtered. The use of gene set enrichment analysis is one way to introduce biological information in order to improve the detection of differentially expressed genes and pathways. In this paper we show that the use of network models while still subject to the problems of normalization is a more robust method for detecting pathways that are differentially overrepresented in lung cancer data. Such differences may provide opportunities for novel therapeutics. In addition, we present evidence that non-small cell lung carcinoma is not a series of homogeneous diseases; rather that there is a heterogeny within the genotype which defies phenotype classification. This diversity helps to explain the lack of progress in developing therapies against non-small cell carcinoma and suggests that drug development may consider multiple pathways as treatment targets

Deletion of a Single beta-Catenin Allele in Osteocytes Abolishes the Bone Anabolic Response to Loading

The Wnt/β-catenin signaling pathway is essential for bone cell viability and function and for skeletal integrity. To determine if β-catenin in osteocytes plays a role in the bone anabolic response to mechanical loading, 18- to 24-week-old osteocyte β-catenin haploinsufficient mice (Dmp1-Cre × β-catenin fl/ + ; HET cKO) were compared with their β-catenin fl/fl (control) littermates. Trabecular bone volume (BV/TV) was significantly less (58.3%) in HET cKO females versus controls, whereas male HET cKO and control mice were not significantly different. Trabecular number was significantly less in HET cKO mice compared with controls for both genders, and trabecular separation was greater in female HET cKO mice. Osteoclast surface was significantly greater in female HET cKO mice. Cortical bone parameters in males and females showed subtle or no differences between HET cKO and controls. The right ulnas were loaded in vivo at 100 cycles, 2 Hz, 2500 µϵ, 3 days per week for 3 weeks, and the left ulnas served as nonloaded controls. Calcein and alizarin complexone dihydrate were injected 10 days and 3 days before euthanization, respectively. Micro-computed tomography (µCT) analysis detected an 8.7% and 7.1% increase in cortical thickness in the loaded right ulnas of male and female control mice, respectively, compared with their nonloaded left ulnas. No significant increase in new cortical bone formation was observed in the HET cKO mice. Histomorphometric analysis of control mice showed a significant increase in endocortical and periosteal mineral apposition rate (MAR), bone-formation rate/bone surface (BFR/BS), BFR/BV, and BFR/TV in response to loading, but no significant increases were detected in the loaded HET cKO mice. These data show that deleting a single copy of β-catenin in osteocytes abolishes the anabolic response to loading, that trabecular bone in females is more severely affected and suggest that a critical threshold of β-catenin is required for bone formation in response to mechanical loading