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Intrahepatic bile duct regeneration in mice does not require Hnf6 or Notch signaling through Rbpj.
Walter TJ, Vanderpool C, Cast AE, Huppert SS
(2014) Am J Pathol 184: 1479-88
MeSH Terms: Animals, Bile Ducts, Intrahepatic, Epithelial Cells, Hepatocyte Nuclear Factor 6, Hepatocytes, Imaging, Three-Dimensional, Immunoglobulin J Recombination Signal Sequence-Binding Protein, Immunohistochemistry, Keratin-19, Mice, Knockout, Plant Lectins, Portal Vein, Receptors, Notch, Regeneration, SOX9 Transcription Factor
Show Abstract · Added May 27, 2014
The potential for intrahepatic bile duct (IHBD) regeneration in patients with bile duct insufficiency diseases is poorly understood. Notch signaling and Hnf6 have each been shown to be important for the morphogenesis of IHBDs in mice. One congenital pediatric liver disease characterized by reduced numbers of IHBDs, Alagille syndrome, is associated with mutations in Notch signaling components. Therefore, we investigated whether liver cell plasticity could contribute to IHBD regeneration in mice with disruptions in Notch signaling and Hnf6. We studied a mouse model of bile duct insufficiency with liver epithelial cell-specific deficiencies in Hnf6 and Rbpj, a mediator of canonical Notch signaling. Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice initially developed no peripheral bile ducts. The evolving postnatal liver phenotype was analyzed using IHBD resin casting, immunostaining, and serum chemistry. With age, Albumin-Cre Hnf6(flox/flox)Rbpj(flox/flox) mice mounted a ductular reaction extending through the hepatic tissue and then regenerated communicating peripheral IHBD branches. Rbpj and Hnf6 were determined to remain absent from biliary epithelial cells constituting the ductular reaction and the regenerated peripheral IHBDs. We report the expression of Sox9, a marker of biliary epithelial cells, in cells expressing hepatocyte markers. Tissue analysis indicates that reactive ductules did not arise directly from preexisting hilar IHBDs. We conclude that liver cell plasticity is competent for regeneration of IHBDs independent of Notch signaling via Rbpj and Hnf6.
Copyright © 2014 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
0 Communities
1 Members
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15 MeSH Terms
Jagged1 is essential for osteoblast development during maxillary ossification.
Hill CR, Yuasa M, Schoenecker J, Goudy SL
(2014) Bone 62: 10-21
MeSH Terms: Animals, Bone Density, Bone Morphogenetic Proteins, Calcification, Physiologic, Calcium, Calcium-Binding Proteins, Cell Differentiation, Embryo, Mammalian, Intercellular Signaling Peptides and Proteins, Jagged-1 Protein, Maxilla, Membrane Proteins, Mesoderm, Mice, Knockout, Organ Size, Osteoblasts, Osteogenesis, Palate, Receptors, Fc, Receptors, Notch, Serrate-Jagged Proteins, Signal Transduction, X-Ray Microtomography
Show Abstract · Added May 28, 2014
Maxillary hypoplasia occurs due to insufficient maxillary intramembranous ossification, leading to poor dental occlusion, respiratory obstruction and cosmetic deformities. Conditional deletion of Jagged1 (Jag1) in cranial neural crest (CNC) cells using Wnt1-cre; Jagged1(f/f) (Jag1CKO) led to maxillary hypoplasia characterized by intrinsic differences in bone morphology and density using μCT evaluation. Jag1CKO maxillas revealed altered collagen deposition, delayed ossification, and reduced expression of early and late determinants of osteoblast development during maxillary ossification. In vitro bone cultures on Jag1CKO mouse embryonic maxillary mesenchymal (MEMM) cells demonstrated decreased mineralization that was also associated with diminished induction of osteoblast determinants. BMP receptor expression was dysregulated in the Jag1CKO MEMM cells suggesting that these cells were unable to respond to BMP-induced differentiation. JAG1-Fc rescued in vitro mineralization and osteoblast gene expression changes. These data suggest that JAG1 signaling in CNC-derived MEMM cells is required for osteoblast development and differentiation during maxillary ossification.
Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
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23 MeSH Terms
Matrix metalloproteinase-9 inhibition improves proliferation and engraftment of myogenic cells in dystrophic muscle of mdx mice.
Hindi SM, Shin J, Ogura Y, Li H, Kumar A
(2013) PLoS One 8: e72121
MeSH Terms: Animals, Cell Proliferation, Cells, Cultured, Graft Survival, Macrophages, Matrix Metalloproteinase 9, Matrix Metalloproteinase Inhibitors, Mice, Mice, Inbred C57BL, Mice, Inbred mdx, Mice, Knockout, Muscle, Skeletal, Muscular Dystrophy, Duchenne, Myoblasts, Phenotype, Primary Cell Culture, Receptors, Notch, Wnt Signaling Pathway
Show Abstract · Added March 3, 2014
Duchenne muscular dystrophy (DMD) caused by loss of cytoskeletal protein dystrophin is a devastating disorder of skeletal muscle. Primary deficiency of dystrophin leads to several secondary pathological changes including fiber degeneration and regeneration, extracellular matrix breakdown, inflammation, and fibrosis. Matrix metalloproteinases (MMPs) are a group of extracellular proteases that are involved in tissue remodeling, inflammation, and development of interstitial fibrosis in many disease states. We have recently reported that the inhibition of MMP-9 improves myopathy and augments myofiber regeneration in mdx mice (a mouse model of DMD). However, the mechanisms by which MMP-9 regulates disease progression in mdx mice remain less understood. In this report, we demonstrate that the inhibition of MMP-9 augments the proliferation of satellite cells in dystrophic muscle. MMP-9 inhibition also causes significant reduction in percentage of M1 macrophages with concomitant increase in the proportion of promyogenic M2 macrophages in mdx mice. Moreover, inhibition of MMP-9 increases the expression of Notch ligands and receptors, and Notch target genes in skeletal muscle of mdx mice. Furthermore, our results show that while MMP-9 inhibition augments the expression of components of canonical Wnt signaling, it reduces the expression of genes whose products are involved in activation of non-canonical Wnt signaling in mdx mice. Finally, the inhibition of MMP-9 was found to dramatically improve the engraftment of transplanted myoblasts in skeletal muscle of mdx mice. Collectively, our study suggests that the inhibition of MMP-9 is a promising approach to stimulate myofiber regeneration and improving engraftment of muscle progenitor cells in dystrophic muscle.
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18 MeSH Terms
Claudin-1 regulates intestinal epithelial homeostasis through the modulation of Notch-signalling.
Pope JL, Bhat AA, Sharma A, Ahmad R, Krishnan M, Washington MK, Beauchamp RD, Singh AB, Dhawan P
(2014) Gut 63: 622-34
MeSH Terms: Animals, Apoptosis, Cell Differentiation, Cell Proliferation, Claudin-1, Colitis, Colon, Dextran Sulfate, Disease Models, Animal, Homeostasis, Intestinal Mucosa, Mice, Mice, Inbred C57BL, Mice, Transgenic, Real-Time Polymerase Chain Reaction, Receptors, Notch, Signal Transduction
Show Abstract · Added January 20, 2014
OBJECTIVE - Claudin-1 expression is increased and dysregulated in colorectal cancer and causally associates with the dedifferentiation of colonic epithelial cells, cancer progression and metastasis. Here, we have sought to determine the role claudin-1 plays in the regulation of intestinal epithelial homeostasis.
DESIGN - We have used a novel villin-claudin-1 transgenic (Cl-1Tg) mouse as model (with intestinal claudin-1 overexpression). The effect of claudin-1 expression upon colonic epithelial differentiation, lineage commitment and Notch-signalling was determined using immunohistochemical, immunoblot and real-time PCR analysis. The frequently used mouse model of dextran sodium sulfate (DSS)-colitis was used to model inflammation, injury and repair.
RESULTS - In Cl-1Tg mice, normal colonocyte differentiation programme was disrupted and goblet cell number and mucin-2 (muc-2) expressions were significantly downregulated while Notch- and ERK1/2-signalling were upregulated, compared with the wild type-littermates. Cl-1Tg mice were also susceptible to colonic inflammation and demonstrated impaired recovery and hyperproliferation following the DSS-colitis. Our data further show that claudin-1 regulates Notch-signalling through the regulation of matrix metalloproteinase-9 (MMP-9) and p-ERK signalling to regulate proliferation and differentiation.
CONCLUSIONS - Claudin-1 helps regulate intestinal epithelial homeostasis through the regulation of Notch-signalling. An upregulated claudin-1 expression induces MMP-9 and p-ERK signalling to activate Notch-signalling, which in turn inhibits the goblet cell differentiation. Decreased goblet cell number decreases muc-2 expression and thus enhances susceptibility to mucosal inflammation. Claudin-1 expression also induces colonic epithelial proliferation in a Notch-dependent manner. Our findings may help understand the role of claudin-1 in the regulation of inflammatory bowel diseases and CRC.
1 Communities
7 Members
0 Resources
17 MeSH Terms
T cell-specific notch inhibition blocks graft-versus-host disease by inducing a hyporesponsive program in alloreactive CD4+ and CD8+ T cells.
Sandy AR, Chung J, Toubai T, Shan GT, Tran IT, Friedman A, Blackwell TS, Reddy P, King PD, Maillard I
(2013) J Immunol 190: 5818-28
MeSH Terms: Animals, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cytotoxicity, Immunologic, Enzyme Activation, Gene Expression Regulation, Graft vs Host Disease, Interferon-gamma, Lymphocyte Activation, Mice, Mitogen-Activated Protein Kinases, NF-kappa B, Proto-Oncogene Proteins p21(ras), Receptors, Notch, T-Box Domain Proteins, T-Lymphocytes, Regulatory
Show Abstract · Added March 7, 2014
Graft-versus-host disease (GVHD) induced by donor-derived T cells remains the major limitation of allogeneic bone marrow transplantation (allo-BMT). We previously reported that the pan-Notch inhibitor dominant-negative form of Mastermind-like 1 (DNMAML) markedly decreased the severity and mortality of acute GVHD mediated by CD4(+) T cells in mice. To elucidate the mechanisms of Notch action in GVHD and its role in CD8(+) T cells, we studied the effects of Notch inhibition in alloreactive CD4(+) and CD8(+) T cells using mouse models of allo-BMT. DNMAML blocked GVHD induced by either CD4(+) or CD8(+) T cells. Both CD4(+) and CD8(+) Notch-deprived T cells had preserved expansion in lymphoid organs of recipients, but profoundly decreased IFN-γ production despite normal T-bet and enhanced Eomesodermin expression. Alloreactive DNMAML T cells exhibited decreased Ras/MAPK and NF-κB activity upon ex vivo restimulation through the TCR. In addition, alloreactive T cells primed in the absence of Notch signaling had increased expression of several negative regulators of T cell activation, including Dgka, Cblb, and Pdcd1. DNMAML expression had modest effects on in vivo proliferation but preserved overall alloreactive T cell expansion while enhancing accumulation of pre-existing natural regulatory T cells. Overall, DNMAML T cells acquired a hyporesponsive phenotype that blocked cytokine production but maintained their expansion in irradiated allo-BMT recipients, as well as their in vivo and ex vivo cytotoxic potential. Our results reveal parallel roles for Notch signaling in alloreactive CD4(+) and CD8(+) T cells that differ from past reports of Notch action and highlight the therapeutic potential of Notch inhibition in GVHD.
1 Communities
1 Members
0 Resources
16 MeSH Terms
The transcriptional repressor NKAP is required for the development of iNKT cells.
Thapa P, Das J, McWilliams D, Shapiro M, Sundsbak R, Nelson-Holte M, Tangen S, Anderson J, Desiderio S, Hiebert S, Sant'angelo DB, Shapiro VS
(2013) Nat Commun 4: 1582
MeSH Terms: Animals, Cell Survival, Gene Deletion, Gene Rearrangement, alpha-Chain T-Cell Antigen Receptor, Histone Deacetylases, Mice, Mice, Knockout, Natural Killer T-Cells, Organ Specificity, Receptors, Antigen, T-Cell, alpha-beta, Receptors, Notch, Recombination, Genetic, Repressor Proteins, Thymocytes
Show Abstract · Added March 26, 2014
Invariant natural killer T cells have a distinct developmental pathway from conventional αβ T cells. Here we demonstrate that the transcriptional repressor NKAP is required for invariant natural killer T cell but not conventional T cell development. In CD4-cre NKAP conditional knockout mice, invariant natural killer T cell development is blocked at the double-positive stage. This cell-intrinsic block is not due to decreased survival or failure to rearrange the invariant Vα14-Jα18 T cell receptor-α chain, but is rescued by overexpression of a rec-Vα14-Jα18 transgene at the double-positive stage, thus defining a role for NKAP in selection into the invariant natural killer T cell lineage. Importantly, deletion of the NKAP-associated protein histone deacetylase 3 causes a similar block in the invariant natural killer T cell development, indicating that NKAP and histone deacetylase 3 functionally interact to control invariant natural killer T cell development.
1 Communities
1 Members
0 Resources
14 MeSH Terms
Partial promoter substitutions generating transcriptional sentinels of diverse signaling pathways in embryonic stem cells and mice.
Serup P, Gustavsen C, Klein T, Potter LA, Lin R, Mullapudi N, Wandzioch E, Hines A, Davis A, Bruun C, Engberg N, Petersen DR, Peterslund JM, Macdonald RJ, Grapin-Botton A, Magnuson MA, Zaret KS
(2012) Dis Model Mech 5: 956-66
MeSH Terms: Activins, Animals, Base Sequence, Bone Morphogenetic Proteins, Embryo, Mammalian, Embryonic Stem Cells, Genetic Engineering, Genetic Loci, Humans, Mice, Molecular Sequence Data, Mutation, Promoter Regions, Genetic, Proteins, RNA, Untranslated, Rats, Receptors, Notch, Recombination, Genetic, Response Elements, Sequence Deletion, Signal Transduction, Transcription, Genetic, Tretinoin, Wnt Signaling Pathway
Show Abstract · Added November 6, 2013
Extracellular signals in development, physiology, homeostasis and disease often act by regulating transcription. Herein we describe a general method and specific resources for determining where and when such signaling occurs in live animals and for systematically comparing the timing and extent of different signals in different cellular contexts. We used recombinase-mediated cassette exchange (RMCE) to test the effect of successively deleting conserved genomic regions of the ubiquitously active Rosa26 promoter and substituting the deleted regions for regulatory sequences that respond to diverse extracellular signals. We thereby created an allelic series of embryonic stem cells and mice, each containing a signal-responsive sentinel with different fluorescent reporters that respond with sensitivity and specificity to retinoic acids, bone morphogenic proteins, activin A, Wnts or Notch, and that can be adapted to any pathway that acts via DNA elements.
3 Communities
2 Members
10 Resources
24 MeSH Terms
Uncovering MicroRNA and Transcription Factor Mediated Regulatory Networks in Glioblastoma.
Sun J, Gong X, Purow B, Zhao Z
(2012) PLoS Comput Biol 8: e1002488
MeSH Terms: Brain Neoplasms, Computational Biology, Databases, Genetic, Gene Expression Profiling, Gene Regulatory Networks, Glioblastoma, Humans, MicroRNAs, Oligonucleotide Array Sequence Analysis, Receptors, Notch, Signal Transduction, Transcription Factors
Show Abstract · Added March 5, 2014
Glioblastoma multiforme (GBM) is the most common and lethal brain tumor in humans. Recent studies revealed that patterns of microRNA (miRNA) expression in GBM tissue samples are different from those in normal brain tissues, suggesting that a number of miRNAs play critical roles in the pathogenesis of GBM. However, little is yet known about which miRNAs play central roles in the pathology of GBM and their regulatory mechanisms of action. To address this issue, in this study, we systematically explored the main regulation format (feed-forward loops, FFLs) consisting of miRNAs, transcription factors (TFs) and their impacting GBM-related genes, and developed a computational approach to construct a miRNA-TF regulatory network. First, we compiled GBM-related miRNAs, GBM-related genes, and known human TFs. We then identified 1,128 3-node FFLs and 805 4-node FFLs with statistical significance. By merging these FFLs together, we constructed a comprehensive GBM-specific miRNA-TF mediated regulatory network. Then, from the network, we extracted a composite GBM-specific regulatory network. To illustrate the GBM-specific regulatory network is promising for identification of critical miRNA components, we specifically examined a Notch signaling pathway subnetwork. Our follow up topological and functional analyses of the subnetwork revealed that six miRNAs (miR-124, miR-137, miR-219-5p, miR-34a, miR-9, and miR-92b) might play important roles in GBM, including some results that are supported by previous studies. In this study, we have developed a computational framework to construct a miRNA-TF regulatory network and generated the first miRNA-TF regulatory network for GBM, providing a valuable resource for further understanding the complex regulatory mechanisms in GBM. The observation of critical miRNAs in the Notch signaling pathway, with partial verification from previous studies, demonstrates that our network-based approach is promising for the identification of new and important miRNAs in GBM and, potentially, other cancers.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Mind bomb 1 is required for pancreatic β-cell formation.
Horn S, Kobberup S, Jørgensen MC, Kalisz M, Klein T, Kageyama R, Gegg M, Lickert H, Lindner J, Magnuson MA, Kong YY, Serup P, Ahnfelt-Rønne J, Jensen JN
(2012) Proc Natl Acad Sci U S A 109: 7356-61
MeSH Terms: Animals, Basic Helix-Loop-Helix Transcription Factors, Blotting, Western, Cell Lineage, Embryo, Mammalian, Female, Gene Expression Regulation, Developmental, Hepatocyte Nuclear Factor 1-beta, Hepatocyte Nuclear Factor 3-beta, Homeodomain Proteins, Insulin-Secreting Cells, Male, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Mutation, Nerve Tissue Proteins, Nuclear Proteins, Pancreas, Receptors, Notch, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Time Factors, Transcription Factors, Ubiquitin-Protein Ligases
Show Abstract · Added December 5, 2013
During early pancreatic development, Notch signaling represses differentiation of endocrine cells and promotes proliferation of Nkx6-1(+)Ptf1a(+) multipotent progenitor cells (MPCs). Later, antagonistic interactions between Nkx6 transcription factors and Ptf1a function to segregate MPCs into distal Nkx6-1(-)Ptf1a(+) acinar progenitors and proximal Nkx6-1(+)Ptf1a(-) duct and β-cell progenitors. Distal cells are initially multipotent, but evolve into unipotent, acinar cell progenitors. Conversely, proximal cells are bipotent and give rise to duct cells and late-born endocrine cells, including the insulin producing β-cells. However, signals that regulate proximodistal (P-D) patterning and thus formation of β-cell progenitors are unknown. Here we show that Mind bomb 1 (Mib1) is required for correct P-D patterning of the developing pancreas and β-cell formation. We found that endoderm-specific inactivation of Mib1 caused a loss of Nkx6-1(+)Ptf1a(-) and Hnf1β(+) cells and a corresponding loss of Neurog3(+) endocrine progenitors and β-cells. An accompanying increase in Nkx6-1(-)Ptf1a(+) and amylase(+) cells, occupying the proximal domain, suggests that proximal cells adopt a distal fate in the absence of Mib1 activity. Impeding Notch-mediated transcriptional activation by conditional expression of dominant negative Mastermind-like 1 (Maml1) resulted in a similarly distorted P-D patterning and suppressed β-cell formation, as did conditional inactivation of the Notch target gene Hes1. Our results reveal iterative use of Notch in pancreatic development to ensure correct P-D patterning and adequate β-cell formation.
3 Communities
2 Members
1 Resources
26 MeSH Terms
Vital roles of mTOR complex 2 in Notch-driven thymocyte differentiation and leukemia.
Lee K, Nam KT, Cho SH, Gudapati P, Hwang Y, Park DS, Potter R, Chen J, Volanakis E, Boothby M
(2012) J Exp Med 209: 713-28
MeSH Terms: Active Transport, Cell Nucleus, Animals, Carrier Proteins, Cell Differentiation, Cell Lineage, Forkhead Box Protein O1, Forkhead Transcription Factors, Mice, Mice, Inbred C57BL, NF-kappa B, Precursor T-Cell Lymphoblastic Leukemia-Lymphoma, Protein-Serine-Threonine Kinases, Proto-Oncogene Proteins c-akt, Rapamycin-Insensitive Companion of mTOR Protein, Receptors, Notch, TOR Serine-Threonine Kinases, Thymocytes
Show Abstract · Added December 10, 2013
Notch plays critical roles in both cell fate decisions and tumorigenesis. Notch receptor engagement initiates signaling cascades that include a phosphatidylinositol 3-kinase/target of rapamycin (TOR) pathway. Mammalian TOR (mTOR) participates in two distinct biochemical complexes, mTORC1 and mTORC2, and the relationship between mTORC2 and physiological outcomes dependent on Notch signaling is unknown. In this study, we report contributions of mTORC2 to thymic T-cell acute lymphoblastic leukemia (T-ALL) driven by Notch. Conditional deletion of Rictor, an essential component of mTORC2, impaired Notch-driven proliferation and differentiation of pre-T cells. Furthermore, NF-κB activity depended on the integrity of mTORC2 in thymocytes. Active Akt restored NF-κB activation, a normal rate of proliferation, and differentiation of Rictor-deficient pre-T cells. Strikingly, mTORC2 depletion lowered CCR7 expression in thymocytes and leukemic cells, accompanied by decreased tissue invasion and delayed mortality in T-ALL driven by Notch. Collectively, these findings reveal roles for mTORC2 in promoting thymic T cell development and T-ALL and indicate that mTORC2 is crucial for Notch signaling to regulate Akt and NF-κB.
2 Communities
3 Members
0 Resources
17 MeSH Terms