Characterization of Mice with Targeted Deletion of the Gene Encoding Core 2 β1,6-N-Acetylglucosaminyltransferase-2

Stone, Erica L.; Lee, Seung Ho; Ismail, Mohd Nazri; Fukuda, Minoru

doi:10.1016/s0076-6879(10)79009-1

Cited by 15 publications

(10 citation statements)

References 38 publications

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“…Among early target genes, we found known inhibitors of cytokine signaling, suppressor of cytokine signaling 1 ( SOCS1 ) and cytokine inducible SH2-containing protein ( CISH ), which can provide a negative feedback loop for cytokine signaling 20 . We also detected genes such as hyaluronan synthase 3 ( HAS3 ), heparan sulfate (glucosamine) 3-O-sulfotransferase 1 ( HS3ST1 ), and glucosaminyl (N-acetyl) transferase 3, mucin type ( GCNT3 ), which are involved in the synthesis of unbranched glycosaminoglycan hyaluronan, heparan sulfate, and mucin, major constituents of the epithelial extracellular environment 21 – 23 . These genes have been previously identified in EoE biopsies and in primary human esophageal epithelial cells induced with IL-13 10 , 19 .…”

Section: Resultsmentioning

confidence: 99%

Neurotrophic tyrosine kinase receptor 1 is a direct transcriptional and epigenetic target of IL-13 involved in allergic inflammation

et al. 2015

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Although IL-13 and neurotrophins are functionally important for the pathogenesis of immune responses, the interaction of these pathways has not been explored. Herein, by interrogating IL-13–induced responses in human epithelial cells we show that neurotrophic tyrosine kinase receptor, type 1 (NTRK1), a cognate, high-affinity receptor for nerve growth factor (NGF), is an early transcriptional IL-13 target. Induction of NTRK1 was accompanied by accumulation of activating epigenetic marks in the promoter; transcriptional and epigenetic changes were STAT6-dependent. Using eosinophilic esophagitis (EoE) as a model for human allergic inflammation, we found that NTRK1 was increased in inflamed tissue, dynamically expressed as a function of disease activity, and the downstream mediator of NTRK1 signaling early growth response 1 (EGR1) protein was elevated in allergic inflammatory tissue compared with control tissue. Unlike NTRK1, its ligand NGF was constitutively expressed in control and disease states, indicating that IL-13–stimulated NTRK1 induction is a limiting factor in pathway activation. In epithelial cells, NGF and IL-13 synergistically induced several target genes, including CCL26 (eotaxin-3). In summary, we have demonstrated that IL-13 confers epithelial cell responsiveness to NGF by regulating NTRK1 levels by a transcriptional and epigenetic mechanism and that this process likely contributes to allergic inflammation.

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Section: Resultsmentioning

confidence: 99%

Neurotrophic tyrosine kinase receptor 1 is a direct transcriptional and epigenetic target of IL-13 involved in allergic inflammation

et al. 2015

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“…ablation of Syt7 in mice resulted in inflammatory myopathy (46); C2GnT2 KO mice have decreased mucosal barrier function in the digestive tract, reduced levels of circulating IgGs and fecal IgA, and increased susceptibility to experimental colitis (47), and complement deficiency is associated with lupus (48). We speculate that the downregulation of these anti-inflammatory/regulatory genes in the innate immune system or in cholangiocytes makes it difficult to resolve inflammatory responses, which may facilitate the generation of neoantigen in the target tissue.…”

Section: Discussionmentioning

confidence: 99%

A Novel Pkhd1 Mutation Interacts with the Nonobese Diabetic Genetic Background To Cause Autoimmune Cholangitis

Huang

Rainbow

et al. 2018

The Journal of Immunology

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We previously published that NOD.c3c4 mice develop spontaneous autoimmune biliary disease (ABD) with anti-mitochondrial antibodies, histopathological lesions, and autoimmune T lymphocytes similar to human primary biliary cholangitis (PBC). Here we demonstrate that ABD in NOD.c3c4 and related NOD ABD strains is caused by a chromosome 1 region that includes a novel mutation in Polycystic kidney and hepatic disease 1 (Pkhd1). We show that an LTR element inserted into intron 35 exposes an alternative polyadenylation site, resulting in a truncated Pkhd1 transcript. A novel NOD congenic mouse expressing aberrant Pkhd1, but lacking the c3 and c4 chromosomal regions (“NOD.Abd3”), reproduces the immunopathological features of NOD ABD. RNA-seq of NOD.Abd3 common bile duct early in disease demonstrates upregulation of genes involved in cholangiocyte injury/morphology and downregulation of immunoregulatory genes. Consistent with this, bone marrow chimera studies show that aberrant Pkhd1 must be expressed in both the target tissue (cholangiocytes) and the immune system (bone marrow). Mutations of Pkhd1 produce biliary abnormalities in mice, but have not been previously associated with autoimmunity. Here we eliminate clinical biliary disease by backcrossing this Pkhd1 mutation onto the B6 genetic background: thus the NOD genetic background (which promotes autoimmunity) is essential for disease. We propose that loss of functional Pkhd1 on the NOD background produces early bile duct abnormalities, initiating a break in tolerance that leads to autoimmune cholangitis in NOD.Abd3 congenic mice. This model is important for understanding loss of tolerance to cholangiocytes and is relevant to the pathogenesis of several human cholangiopathies.

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“…Importantly, GCNT3-deficient mice are viable and fertile, despite some defects in immune functions. 40 Thus, transient inhibition of GCNT3 is likely to be well tolerated.…”

Section: Discussionmentioning

confidence: 99%

Erratum: An RNA interference screen identifies new avenues for nephroprotection

et al. 2016

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Acute kidney injury is a major public health problem, which is commonly caused by renal ischemia and is associated with a high risk of mortality and long-term disability. Efforts to develop a treatment for this condition have met with very limited success. We used an RNA interference screen to identify genes (BCL2L14, BLOC1S2, C2ORF42, CPT1A, FBP1, GCNT3, RHOB, SCIN, TACR1, and TNFAIP6) whose suppression improves survival of kidney epithelial cells in in vitro models of oxygen and glucose deprivation. Some of the genes also modulate the toxicity of cisplatin, an anticancer agent whose use is currently limited by nephrotoxicity. Furthermore, pharmacological inhibition of TACR1 product NK1R was protective in a model of mouse renal ischemia, attesting to the in vivo relevance of our findings. These data shed new light on the mechanisms of stress response in mammalian cells, and open new avenues to reduce the morbidity and mortality associated with renal injury.

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Characterization of Mice with Targeted Deletion of the Gene Encoding Core 2 β1,6-N-Acetylglucosaminyltransferase-2

Cited by 15 publications

References 38 publications

Neurotrophic tyrosine kinase receptor 1 is a direct transcriptional and epigenetic target of IL-13 involved in allergic inflammation

Neurotrophic tyrosine kinase receptor 1 is a direct transcriptional and epigenetic target of IL-13 involved in allergic inflammation

A Novel Pkhd1 Mutation Interacts with the Nonobese Diabetic Genetic Background To Cause Autoimmune Cholangitis

Erratum: An RNA interference screen identifies new avenues for nephroprotection

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