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Siggs O.M.,Scripps Research Institute | Siggs O.M.,University of Oxford | Beutler B.,Center for Genetics of Host Defense
Cell Cycle | Year: 2012

The BTB-ZF (broad-complex, tramtrack and bric-à-brac - zinc finger) proteins are encoded by at least 49 genes in mouse and man and commonly serve as sequence-specific silencers of gene expression. This review will focus on the known physiological functions of mammalian BTB-ZF proteins, which include essential roles in the development of the immune system. We discuss their function in terminally differentiated lymphocytes and the progenitors that give rise to them, their action in hematopoietic malignancy and roles beyond the immune system. © 2012 Landes Bioscience. Source

Brandl K.,University of California at San Diego | Beutler B.,Center for Genetics of Host Defense
Current Opinion in Immunology | Year: 2012

Inflammatory bowel diseases (IBD), including both ulcerative colitis and Crohn's disease, are extremely variable in severity and have strong genetic components. In mice, several mutations are known to favor or inhibit intestinal inflammation. But a comprehensive picture of the pathogenesis of IBD cannot be assembled based on the limited information so far available from mouse genetic analyses, nor can human IBD be stringently ascribed to mutations known to be influential in mice. This review highlights recent progress made using mouse models created through a forward genetic approach towards the understanding of genes that normally prevent intestinal inflammation. © 2012 Elsevier Ltd. Source

Jimenez-Dalmaroni M.J.,University of Oxford | Jimenez-Dalmaroni M.J.,Scripps Research Institute | Radcliffe C.M.,University of Oxford | Radcliffe C.M.,Biologics | And 13 more authors.
Innate Immunity | Year: 2015

TLRs are key innate immune receptors that recognize conserved features of biological molecules that are found in microbes. In particular, TLR2 has been reported to be activated by different kinds of microbial ligands. To advance our understanding of the interaction of TLR2 with its ligands, the recombinant human TLR2 ectodomain (hTLR2ED) was expressed using a baculovirus/insect cell expression system and its biochemical, as well as ligand binding, properties were investigated. The hTLR2ED binds synthetic bacterial and mycoplasmal lipopeptides, lipoteichoic acid from Staphylococcus aureus, and synthetic lipoarabinomannan precursors from Mycobacterium at extracellular physiological conditions, in the absence of its co-receptors TLR1 and TLR6. We also determined that lipopeptides and glycolipids cannot bind simultaneously to hTLR2ED and that the phosphatidyl inositol mannoside 2 (Pim2) is the minimal lipoarabinomannan structure for binding to hTLR2ED. Binding of hTLR2ED to Pim4, which contains a diacylglycerol group with one of its acyl chains containing 19 carbon atoms, indicates that hTLR2ED can bind ligands with acyl chains longer than 16 carbon atoms. In summary, our data indicate that diacylglycerol is the ligand moiety of microbial glycolipids and lipoproteins that bind to hTLR2ED and that both types of ligands bind to the same binding site of hTLR2ED. © The Author(s) 2014. Source

Rutschmann S.,Imperial College London | Crozat K.,French Institute of Health and Medical Research | Li X.,Center for Genetics of Host Defense | Hanselman J.C.,Pfizer | And 3 more authors.
G3: Genes, Genomes, Genetics | Year: 2012

The site 1 protease, encoded by Mbtps1, mediates the initial cleavage of site 2 protease substrates, including sterol regulatory element binding proteins and CREB/ATF transcription factors. We demonstrate that a hypomorphic mutation of Mbtps1 called woodrat (wrt) caused hypocholesterolemia, as well as progressive hypopigmentation of the coat, that appears to be mechanistically unrelated. Hypopigmentation was rescued by transgenic expression of wild-type Mbtps1, and reciprocal grafting studies showed that normal pigmentation depended upon both cell-intrinsic or paracrine factors, as well as factors that act systemically, both of which are lacking in wrt homozygotes. Mbtps1 exhibited a maternal-zygotic effect characterized by fully penetrant embryonic lethality of maternal-zygotic wrt mutant offspring and partial embryonic lethality (~40%) of zygotic wrt mutant offspring. Mbtps1 is one of two maternal-zygotic effect genes identified in mammals to date. It functions nonredundantly in pigmentation and embryogenesis. © 2012 Rutschmann et al. Source

Garrison S.R.,Medical College of Wisconsin | Weyer A.D.,Medical College of Wisconsin | Barabas M.E.,Medical College of Wisconsin | Beutler B.A.,Center for Genetics of Host Defense | Stucky C.L.,Medical College of Wisconsin
Pain | Year: 2014

Therapeutic use of general sodium channel blockers, such as lidocaine, can substantially reduce the enhanced activity in sensory neurons that accompanies chronic pain after nerve or tissue injury. However, because these general blockers have significant side effects, there is great interest in developing inhibitors that specifically target subtypes of sodium channels. Moreover, some idiopathic small-fiber neuropathies are driven by gain-of-function mutations in specific sodium channel subtypes. In the current study, we focus on one subtype, the voltage-gated sodium channel 1.8 (Nav1.8). Nav1.8 is preferentially expressed in nociceptors, and gain-of-function mutations in Nav1.8 result in painful mechanical hypersensitivity in humans. Here, we used the recently developed gain-of-function Nav1.8 transgenic mouse strain, Possum, to investigate Nav1.8-mediated peripheral afferent hyperexcitability. This gain-of-function mutation resulted in markedly increased mechanically evoked action potential firing in subclasses of Aβ, Aδ, and C fibers. Moreover, mechanical stimuli initiated bursts of action potential firing in specific subpopulations that continued for minutes after removal of the force and were not susceptible to conduction failure. Surprisingly, despite the intense afferent firing, the behavioral effects of the Nav1.8 mutation were quite modest, as only frankly noxious stimuli elicited enhanced pain behavior. These data demonstrate that a Nav1.8 gain-of-function point mutation contributes to intense hyperexcitability along the afferent axon within distinct sensory neuron subtypes. © 2014 Published by Elsevier B.V. on behalf of International Association for the Study ofPain. All rights reserved. Source

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