SEL1L deficiency impairs growth and differentiation of pancreatic epithelial cells

<p>Abstract</p> <p>Background</p> <p>The vertebrate pancreas contains islet, acinar and ductal cells. These cells derive from a transient pool of multipotent pancreatic progenitors during embryonic development. Insight into the genetic determinants regulating pancreatic organogenesis will help the development of cell-based therapies for the treatment of diabetes mellitus. <it>Suppressor enhancer lin12/Notch 1 like (Sel1l</it>) encodes a cytoplasmic protein that is highly expressed in the developing mouse pancreas. However, the morphological and molecular events regulated by <it>Sel1l </it>remain elusive.</p> <p>Results</p> <p>We have characterized the pancreatic phenotype of mice carrying a gene trap mutation in <it>Sel1l</it>. We show that <it>Sel1l </it>expression in the developing pancreas coincides with differentiation of the endocrine and exocrine lineages. Mice homozygous for the gene trap mutation die prenatally and display an impaired pancreatic epithelial morphology and cell differentiation. The pancreatic epithelial cells of <it>Sel1l </it>mutant embryos are confined to the progenitor cell state throughout the secondary transition. Pharmacological inhibition of Notch signaling partially rescues the pancreatic phenotype of <it>Sel1l </it>mutant embryos.</p> <p>Conclusions</p> <p>Together, these data suggest that <it>Sel1l </it>is essential for the growth and differentiation of endoderm-derived pancreatic epithelial cells during mouse embryonic development.</p

Heat flow in the Western Arctic Ocean (Amerasian Basin)

Author Posting. © American Geophysical Union, 2019. This article is posted here by permission of American Geophysical Union for personal use, not for redistribution. The definitive version was published in Journal of Geophysical Research-Solid Earth 124(8), (2019): 7562-7587, doi: 10.1029/2019JB017587.From 1963 to 1973 the U.S. Geological Survey measured heat flow at 356 sites in the Amerasian Basin (Western Arctic Ocean) from a drifting ice island (T‐3). The resulting measurements, which are unevenly distributed on Alpha‐Mendeleev Ridge and in Canada and Nautilus Basins, greatly expand available heat flow data for the Arctic Ocean. Average T‐3 heat flow is ~54.7 ± 11.3 mW/m2, and Nautilus Basin is the only well‐surveyed area (~13% of data) with significantly higher average heat flow (63.8 mW/m2). Heat flow and bathymetry are not correlated at a large scale, and turbiditic surficial sediments (Canada and Nautilus Basins) have higher heat flow than the sediments that blanket the Alpha‐Mendeleev Ridge. Thermal gradients are mostly near‐linear, implying that conductive heat transport dominates and that near‐seafloor sediments are in thermal equilibrium with overlying bottom waters. Combining the heat flow data with modern seismic imagery suggests that some of the observed heat flow variability may be explained by local changes in lithology or the presence of basement faults that channel circulating seawater. A numerical model that incorporates thermal conductivity variations along a profile from Canada Basin (thick sediment on mostly oceanic crust) to Alpha Ridge (thin sediment over thick magmatic units associated with the High Arctic Large Igneous Province) predicts heat flow slightly lower than that observed on Alpha Ridge. This, along with other observations, implies that circulating fluids modulate conductive heat flow and contribute to high variability in the T‐3 data set.B.V. Marshall of the U.S. Geological Survey (USGS) was critical to the T‐3 heat flow studies and would have been included as a coauthor on this work if he were not deceased. The original T‐3 heat flow data acquisition program was supported by the USGS and by the Naval Arctic Research Laboratory of the Office of Naval Research. Over the decade of USGS research on T‐3 Ice Island, numerous researchers and technical staff, including B.V. Marshall, P. Twichell, D. Scoboria, J. Tailleur, B. Tailleur, and others, spent months on the island and endured difficult and sometimes dangerous conditions to acquire this data set alongside colleagues from other institutions. Outstanding support from the USGS Menlo Park office, transportation and logistics assistance from other U.S. federal government agencies, Arctic expertise supplied by native Alaskan communities, and collaboration with Lamont researchers made this research program possible. B. Lachenbruch and L. Lawver revived interest in this data set in 2016, and they, along with D. Darby and J. K. Hall, provided ancillary information on T‐3 studies. B. Clarke and M. Arsenault assisted with initial data digitization. We thank M. Jakobsson, R. Saltus, and G. Oakey for providing critical shapefiles and other data and R. Jackson and S. Mukasa for clarification on unpublished information. Reviews by J. Hopper, P. Hart, and W. Jokat improved the manuscript, and V. Atnipp Cross and A. Babb were instrumental in completion of data releases. The USGS's Coastal/Marine Hazards and Resources Program supported C.R. and D.H. between 2016 and 2019, and C.R. used office space provided by the Earth Resources Laboratory at the Massachusetts Institute of Technology during completion of this work. Data in Figure 11 were provided by the U.S. Extended Continental Shelf (ECS) Project. The opinions, findings, and conclusions stated herein are those of the authors and the U.S. Geological Survey, but do not necessarily reflect those of the U.S. ECS Project. Any use of trade, firm, or product name is for descriptive purposes only and does not imply endorsement by the U.S. Government. Digital data, metadata, and supporting plots for T‐3 heat flow, navigation, and radiogenic heat content, along with Lamont gravity and magnetics data, are available from Ruppel et al. (2019), and the original T‐3 expedition report with explanatory metadata can be downloaded from Lachenbruch et al. (2019)

Mouse H6 Homeobox 1 (Hmx1) mutations cause cranial abnormalities and reduced body mass

<p>Abstract</p> <p>Background</p> <p>The H6 homeobox genes <it>Hmx1</it>, <it>Hmx2</it>, and <it>Hmx3 </it>(also known as <it>Nkx5-3</it>; <it>Nkx5-2 </it>and <it>Nkx5-1</it>, respectively), compose a family within the NKL subclass of the ANTP class of homeobox genes. Hmx gene family expression is mostly limited to sensory organs, branchial (pharyngeal) arches, and the rostral part of the central nervous system. Targeted mutation of either <it>Hmx2 </it>or <it>Hmx3 </it>in mice disrupts the vestibular system. These tandemly duplicated genes have functional overlap as indicated by the loss of the entire vestibular system in double mutants. Mutants have not been described for <it>Hmx1</it>, the most divergent of the family.</p> <p>Results</p> <p>Dumbo (<it>dmbo</it>) is a semi-lethal mouse mutation that was recovered in a forward genetic mutagenesis screen. Mutants exhibit enlarged ear pinnae with a distinctive ventrolateral shift. Here, we report on the basis of this phenotype and other abnormalities in the mutant, and identify the causative mutation as being an allele of <it>Hmx1</it>. Examination of dumbo skulls revealed only subtle changes in cranial bone morphology, namely hyperplasia of the gonial bone and irregularities along the caudal border of the squamous temporal bone. Other nearby otic structures were unaffected. The semilethality of <it>dmbo/dmbo </it>mice was found to be ~40%, occured perinatally, and was associated with exencephaly. Surviving mutants of both sexes exhibited reduced body mass from ~3 days postpartum onwards. Most dumbo adults were microphthalmic. Recombinant animals and specific deletion-bearing mice were used to map the <it>dumbo </it>mutation to a 1.8 Mb region on Chromosome 5. DNA sequencing of genes in this region revealed a nonsense mutation in the first exon of H6 Homeobox 1 (<it>Hmx1</it>; also <it>Nkx5-3</it>). An independent spontaneous allele called misplaced ears (<it>mpe</it>) was also identified, confirming <it>Hmx1 </it>as the responsible mutant gene.</p> <p>Conclusion</p> <p>The divergence of <it>Hmx1 </it>from its paralogs is reflected by different and diverse developmental roles exclusive of vestibular involvement. Additionally, these mutant <it>Hmx1 </it>alleles represent the first mouse models of a recently-discovered Oculo-Auricular syndrome caused by mutation of the orthologous human gene.</p

Common Polymorphisms at the <i>CYP17A1 </i>Locus Associate With Steroid Phenotype:Support for Blood Pressure Genome-Wide Association Study Signals at This Locus

Genome-wide association studies implicate the CYP17A1 gene in human blood pressure regulation although the causative polymorphisms are as yet unknown. We sought to identify common polymorphisms likely to explain this association. We sequenced the CYP17A1 locus in 60 normotensive individuals and observed 24 previously identified single-nucleotide polymorphisms with minor allele frequency &gt;0.05. From these, we selected, for further studies, 7 polymorphisms located ≤2 kb upstream of the CYP17A1 transcription start site. In vitro reporter gene assays identified 3 of these (rs138009835, rs2150927, and rs2486758) as having significant functional effects. We then analyzed the association between the 7 polymorphisms and the urinary steroid metabolites in a hypertensive cohort (n=232). Significant associations included that of rs138009835 with aldosterone metabolite excretion; rs2150927 associated with the ratio of tetrahydrodeoxycorticosterone to tetrahydrodeoxycortisol, which we used as an index of 17α-hydroxylation. Linkage analysis showed rs138009835 to be the only 1 of the 7 polymorphisms in strong linkage disequilibrium with the blood pressure–associated polymorphisms identified in the previous studies. In conclusion, we have identified, characterized, and investigated common polymorphisms at the CYP17A1 locus that have functional effects on gene transcription in vitro and associate with corticosteroid phenotype in vivo. Of these, rs138009835—which we associate with changes in aldosterone level—is in strong linkage disequilibrium with polymorphisms linked by genome-wide association studies to blood pressure regulation. This finding clearly has implications for the development of high blood pressure in a large proportion of the population and justifies further investigation of rs138009835 and its effects

High resolution mapping and positional cloning of ENU-induced mutations in the Rw region of mouse chromosome 5

<p>Abstract</p> <p>Background</p> <p>Forward genetic screens in mice provide an unbiased means to identify genes and other functional genetic elements in the genome. Previously, a large scale ENU mutagenesis screen was conducted to query the functional content of a ~50 Mb region of the mouse genome on proximal Chr 5. The majority of phenotypic mutants recovered were embryonic lethals.</p> <p>Results</p> <p>We report the high resolution genetic mapping, complementation analyses, and positional cloning of mutations in the target region. The collection of identified alleles include several with known or presumed functions for which no mutant models have been reported (<it>Tbc1d14</it>, <it>Nol14</it>, <it>Tyms</it>, <it>Cad</it>, <it>Fbxl5</it>, <it>Haus3</it>), and mutations in genes we or others previously reported (<it>Tapt1</it>, <it>Rest</it>, <it>Ugdh</it>, <it>Paxip1</it>, <it>Hmx1, Otoe, Nsun7</it>). We also confirmed the causative nature of a homeotic mutation with a targeted allele, mapped a lethal mutation to a large gene desert, and localized a spermiogenesis mutation to a region in which no annotated genes have coding mutations. The mutation in <it>Tbc1d14 </it>provides the first implication of a critical developmental role for RAB-GAP-mediated protein transport in early embryogenesis.</p> <p>Conclusion</p> <p>This collection of alleles contributes to the goal of assigning biological functions to all known genes, as well as identifying novel functional elements that would be missed by reverse genetic approaches.</p

Cyclooxygenase-2 Polymorphisms, Aspirin Treatment, and Risk for Colorectal Adenoma Recurrence--Data from a Randomized Clinical Trial

Cyclooxygenase-2 (COX-2) catalyzes the rate-limiting step in the production of prostaglandins, potent mediators of inflammation. Chronic inflammation plays an important role in the development and progression of colorectal cancer. Aspirin inhibits COX-2 activity and lowers the risk of colorectal adenomas and cancer. We investigated whether common genetic variation in COX-2 influenced risk of colorectal adenoma recurrence among 979 participants in the Aspirin/Folate Polyp Prevention Study who were randomly assigned to placebo or aspirin and followed for 3 years for the occurrence of new adenomas. Of these participants, 44.2% developed at least one new adenoma during follow-up. Adjusted relative risks (RRs) and 95% confidence intervals (CIs) were calculated to test the association between genetic variation at six COX-2 single nucleotide polymorphisms (SNPs) and adenoma occurrence and interaction with aspirin treatment. Two SNPs were significantly associated with increased adenoma recurrence: for rs5277 homozygous carriers of the minor C allele had a 51% increased risk compared to GG homozygotes (RR=1.51, 95% CI=1.01–2.25), and for rs4648310 heterozygous carriers of the minor G allele had a 37% increased risk compared to AA homozygotes (RR=1.37, 95% CI=1.05–1.79). (There were no minor allele homozygotes.) In stratified analyses, there was suggestive evidence that rs4648319 modified the effect of aspirin. These results support the hypothesis that that COX-2 plays a role in the etiology of colon cancer and may be a target for aspirin chemoprevention and warrant further investigation in other colorectal adenoma and cancer populations

Vitamins B2, B6, and B12 and Risk of New Colorectal Adenomas in a Randomized Trial of Aspirin Use and Folic Acid Supplementation

Folate, other vitamin B cofactors, and genes involved in folate-mediated one-carbon metabolism (FOCM) all may play important roles in colorectal neoplasia. In this study, we examined the associations between dietary and circulating plasma levels of vitamins B2, B6 and B12 and risk colorectal adenomas

Genetic association study of QT interval highlights role for calcium signaling pathways in myocardial repolarization.

The QT interval, an electrocardiographic measure reflecting myocardial repolarization, is a heritable trait. QT prolongation is a risk factor for ventricular arrhythmias and sudden cardiac death (SCD) and could indicate the presence of the potentially lethal mendelian long-QT syndrome (LQTS). Using a genome-wide association and replication study in up to 100,000 individuals, we identified 35 common variant loci associated with QT interval that collectively explain ∼8-10% of QT-interval variation and highlight the importance of calcium regulation in myocardial repolarization. Rare variant analysis of 6 new QT interval-associated loci in 298 unrelated probands with LQTS identified coding variants not found in controls but of uncertain causality and therefore requiring validation. Several newly identified loci encode proteins that physically interact with other recognized repolarization proteins. Our integration of common variant association, expression and orthogonal protein-protein interaction screens provides new insights into cardiac electrophysiology and identifies new candidate genes for ventricular arrhythmias, LQTS and SCD