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Jan Kitajewski - One of the best experts on this subject based on the ideXlab platform.
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Dynamic maternal and fetal Notch activity and expression in placentation
Placenta, 2017Co-Authors: Heather Levin, Carrie J. Shawber, Virginia E. Papaioannou, Jan Kitajewski, Chantae S. Sullivan-pyke, Ronald J. Wapner, Nataki C. DouglasAbstract:Abstract Introduction Murine placentation requires trophoblast Notch2, while the Notch ligand, JAGGED1, is reduced in invasive trophoblasts from women with preeclampsia. However, the placental cells with active Notch signaling and expression of other Notch Proteins and ligands in placentation have yet to be defined. We sought to identify endothelial cell and trophoblast subtypes with canonical Notch signaling in the decidua and placenta and correlate this to expression of Notch Proteins and ligands. Methods Notch reporter transgenic mice were used to define canonical Notch activity and immunofluorescence staining performed to characterize expression of Notch1, 2, 3, 4 and ligands, Delta-like 4 (Dll4) and Jagged1 (Jag1) during early placentation and in the mature placenta. Results Notch signaling is active in maternal and fetal endothelial cells and trophoblasts during early placentation and in the mature placenta. Dll4, Jag1, Notch1, and Notch4 are expressed in maternal vasculature in the decidua. Dll4, Jag1 and Notch1 are expressed in fetal vasculature in the labyrinth. Dll4, Notch2 and Notch4 are co-expressed in the ectoplacental cone. Notch2 and Notch4 are expressed in parietal-trophoblast giant cells and junctional zone trophoblasts with active canonical Notch signaling and in labyrinthine syncytiotrophoblasts and sinusoidal-trophoblast giant cells. Discussion Canonical Notch activity and distinct expression patterns for Notch Proteins and ligands was evident in endothelium and trophoblasts, suggesting Notch1, Notch2, Notch4, Dll4, and Jag1 have distinct and overlapping functions in placentation. Characterization of Notch signaling defects in existing mouse models of preeclampsia may shed light on the role of Notch in developing the preeclampsia phenotype.
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Vascular Notch Proteins and Notch signaling in the peri-implantation mouse uterus
Vascular Cell, 2015Co-Authors: Carrie J. Shawber, Lu Lin, Maria Gnarra, Mark V. Sauer, Virginia E. Papaioannou, Jan Kitajewski, Nataki C. DouglasAbstract:Angiogenesis is essential for uterine decidualization, the progesterone-mediated transformation of the uterus allowing embryo implantation and initiation of pregnancy. In the current study, we define the vasculature, expression of Notch Proteins and Notch ligands, and Notch activity in both endothelial cells and vascular-associated mural cells of blood vessels in the pre-implantation endometrium and post-implantation decidua of the mouse uterus. We used immunofluorescence to determine the expression of Notch in endothelial cells and mural cells by co-staining for the endothelial cell marker, CD31, the pan-mural cell marker, platelet-derived growth factor receptor beta (PDGFR-β), the pericyte markers, neural/glial antigen 2 (NG2) and desmin, or the smooth muscle cell marker, alpha smooth muscle actin (SMA). A fluorescein isothiocyanate-labeled dextran tracer, was used to identify functional peri-implantation vasculature. CBF:H2B-Venus Notch reporter transgenic mice were used to determine Notch activity. Notch signaling is observed in endothelial cells and pericytes in the peri-implantation uterus. Prior to implantation, Notch1, Notch2 and Notch4 and Notch ligand, Delta-like 4 (Dll4) are expressed in capillary endothelial cells, while Notch3 is expressed in the pericytes. Jagged1 is expressed in both capillary endothelial cells and pericytes. After implantation, Notch1, Notch4 and Dll4 are expressed in endothelial cells of newly formed decidual capillaries. Jagged1 is expressed in endothelial cells of spiral arteries and a subset of decidual pericytes. Notch Proteins are not expressed in lymphatic vessels or macrophages in the peri-implantation uterus. We show Notch activity and distinct expression patterns for Notch Proteins and ligands, suggesting unique roles for Notch1, Notch4, Dll4, and Jag1 during decidual angiogenesis and early placentation. These data set the stage for loss-of-function and gain-of-function studies that will determine the cell-type specific requirements for Notch Proteins in decidual angiogenesis and placentation.
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A switch in Notch gene expression parallels stem cell to endothelial transition in infantile hemangioma
Angiogenesis, 2010Co-Authors: June K. Wu, Omotinuwe Adepoju, Dinuka Silva, Keith Baribault, Elisa Boscolo, Joyce Bischoff, Jan KitajewskiAbstract:Background Infantile hemangioma (IH) is the most common benign tumor of infancy, yet its pathogenesis is poorly understood. Notch family members are known to play a role in vascular development during embryogenesis and postnatal tumor angiogenesis, yet the role of Notch signaling in the pathogenesis of IH has not been investigated. This study aims to survey Notch expression in IH. Materials and methods RNA from resected hemangioma tissue and hemangioma-derived stem cells (HemSCs) and endothelial cells (HemECs) was used for gene expression analyses by real-time PCR. Results were confirmed with immunofluorescence for protein expression in tissue. Results Real-time PCR showed that Notch family gene expression in IH is distinct from placenta and skin. Notch3 is expressed in HemSCs, but not in HemECs, indicating Notch3 is downregulated as HemSCs differentiate into HemECs. Moreover, expression of endothelial-associated Notch Proteins, Notch1, Notch4, and Jagged-1 are increased in involuting hemangiomas and HemECs, suggesting that as hemangioma progresses toward involution, it acquires more differentiated endothelium. A subset of cells stained double positive for Notch3 and CD31, pointing to a potential intermediate between the HemSC cellular differentiation into HemEC. Conclusion HemSCs have distinct Notch expression patterns from differentiated HemECs and from normal human endothelial cells. Notch3 is expressed in HemSCs, while Notch1, Notch4, and Jagged-1 have higher expression levels in HemECs. Notch3 was localized to the interstitial cells outside of the nascent vascular channels in proliferating IH tissue sections, but became more apparent in the perivascular cells in involuting IH. In summary, the pattern of Notch gene expression mirrors the progression from immature cells to endothelial-lined vascular channels (i.e., endothelial differentiation) that characterizes the growth and involution of IH.
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Unique patterns of Notch1, Notch4 and Jagged1 expression in ovarian vessels during folliculogenesis and corpus luteum formation.
Gene Expression Patterns, 2005Co-Authors: Marina Vorontchikhina, Carrie J. Shawber, Ralf C Zimmermann, Hongyan Tang, Jan KitajewskiAbstract:Notch signaling functions to regulate cell-fate decisions by modulating differentiation, proliferation, and survival of cells. Notch receptors and ligands are expressed in embryonic vasculature and are required for the remodeling of the primary embryonic vasculature of mice. Here, we characterize the expression patterns of Notch1, Notch4, and Jagged1 Proteins during the process of folliculogenesis and corpus luteum formation in the mouse ovary, an organ with dynamic physiological angiogenic growth. These Notch Proteins and ligand are expressed in a subset of ovarian vessels, including both mature ovarian vasculature as well as angiogenic neovessels. Their expression in the ovary was found in both endothelial and vascular associated mural cells. Our data suggest a complex regulatory role for the Notch signaling pathway during mouse oogenesis and ovarian neovascularization.
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Notch4 int 3 a mammary proto oncogene is an endothelial cell specific mammalian Notch gene
Development, 1996Co-Authors: Hendrik Uyttendaele, Giovanna Marazzi, Guangyu Wu, David Sassoon, Jan KitajewskiAbstract:The int-3 oncogene was identified as a frequent target in Mouse Mammary Tumor Virus (MMTV)-induced mammary carcinomas and encodes the intracellular domain of a novel mouse Notch gene. To investigate the role of the int-3 proto-oncogene in mouse development and carcinogenesis, we isolated cDNA clones corresponding to the entire coding potential of the int-3 proto-oncogene. We propose to name this gene Notch4 and reserve the int-3 nomenclature for references to the oncogenic form. The deduced amino acid sequence of Notch4 contains conserved motifs found in Notch Proteins; however Notch4 has fewer epidermal growth factor (EGF)-like repeats and a shorter intracellular domain than other mouse Notch homologues. Comparison of the coding potential of the int-3 gene to that of Notch4 suggests that loss of the extracellular domain of Notch4 leads to constitutive activation of this murine Notch protein. In situ hybridization revealed that Notch4 transcripts are primarily restricted to endothelial cells in embryonic and adult life. Truncated Notch4 transcripts were detected in post-meiotic male germ cells. The distinct Notch4 protein features and its restricted expression pattern suggests a specific role for Notch4 during development of vertebrate endothelium.
Raphael Kopan - One of the best experts on this subject based on the ideXlab platform.
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Reply to Gaiano et al.: Expression of Notch Proteins in Pyramidal Neurons in Vivo
Journal of Biological Chemistry, 2012Co-Authors: Jin Zheng, Raphael Kopan, Hirotaka Watanabe, Mary Wines-samuelson, Huailong Zhao, Thomas Gridley, Jie ShenAbstract:This is a response to a letter by Gaiano et al. (1) Gaiano et al. (1) argued that the lack of reduction of Notch1 and Notch2 mRNAs and Proteins in the hippocampus and neocortex of conditional knock-out mice at 2 months of age or older could be due to the specific αCaMKII-Cre line used in our study (2) or possible inefficient Cre-mediated recombination at the Notch1 and Notch2 loci. Compared with the T29-1 line of αCaMKII-Cre mice (3) used in their study (4), in which Cre-mediated recombination is restricted specifically to pyramidal neurons in hippocampal area CA1 (3), Cre-mediated recombination occurs broadly in pyramidal neurons of the entire hippocampus and neocortex in our αCaMKII-Cre mice (5), which have been used to inactivate effectively many genes, including presenilin-1 (5), nicastrin, CREB-binding protein, amyloid precursor protein, APLP1, and APLP2, by 2 months of age. Furthermore, Notch1 and Notch2 loci can be excised rapidly and efficiently by Cre recombinase, as shown by our results that Cre-mediated recombination and degradation of existing Notch mRNAs and Proteins are complete within 2–3 days of introduction of the Cre cDNA (2). Our findings are consistent with in situ hybridization data showing predominant localization of Notch1 (6) and Notch2 (2) mRNAs in the germinal areas rather than the hippocampal CA1 and CA3 areas. It is puzzling that Alberi et al. (4) found that Notch1 mRNA is expressed abundantly in pyramidal neurons of the entire hippocampus in wild-type mice and that its mRNA expression is eliminated in the pyramidal neurons of both hippocampal CA1 and CA3 areas using this highly restrictive T29-1 line of αCaMKII-Cre mice (3).
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target selectivity of vertebrate Notch Proteins collaboration between discrete domains and csl binding site architecture determines activation probability
Journal of Biological Chemistry, 2006Co-Authors: Huiteng Cheng, Liwei Chang, Toshiyuki Ohtsuka, Ryoichiro Kageyama, Gary D Stormo, Raphael KopanAbstract:Abstract All four mammalian Notch Proteins interact with a single DNA-binding protein (RBP-jκ), yet they are not equivalent in activating target genes. Parallel assays of three Notch-responsive promoters in several cell lines revealed that relative activation strength is dependent on protein module and promoter context more than the cellular context. Each Notch protein reads binding site orientation and distribution on the promoter differently; Notch1 performs extremely well on paired sites, and Notch3 prefers single sites in conjunction with a proximal zinc finger transcription factor. Although head-head sites can elicit a Notch response on their own, use of CBS (CSL binding site) in tail-tail orientation is context-dependent. Bias for specific DNA elements is achieved by interplay between the N-terminal RAM (RBP-jκ-associated molecule/ankyrin region), which interprets CBS proximity and orientation, and the C-terminal transactivation domain that interacts specifically with the transcription machinery or nearby factors. To confirm the prediction that modular design underscores the evolution of functional divergence between Notch Proteins, we generated a synthetic Notch protein (Notch1 ankyrin with Notch3 transactivation domain) that displayed superior signaling strength on the hes5 promoter. Consistent with the prediction that “preferred” targets (Hes1) should respond faster and at lower Notch concentration than other targets, we showed that Hes5-GFP was extinguished fast and recovered slowly, whereas Hes1-GFP was inhibited late and recovered quickly after a pulse of DAPT in metanephroi cultures.
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Ectodomain shedding and intramembrane cleavage of mammalian Notch Proteins is not regulated through oligomerization.
Journal of Biological Chemistry, 2004Co-Authors: Marc Vooijs, Eric H. Schroeter, Yonghua Pan, Mary Blandford, Raphael KopanAbstract:Abstract Intramembrane cleaving proteases such as site 2 protease, γ-secretase, and signal peptide peptidase hydrolyze peptide bonds within the transmembrane domain (TMD) of signaling molecules such as SREBP, Notch, and HLA-E, respectively. All three enzymes require a prior cleavage at the juxtamembrane region by another protease. It has been proposed that removing the extracellular domain allows dissociation of substrate TMD, held together by the extracellular domain or loop. Using γ-secretase as a model intramembrane cleaving protease and Notch as a model substrate, we investigated whether activating and inactivating mutations in Notch modulate γ-secretase cleavage through changes in oligomerization. We find that although the Notch epidermal growth factor repeats can promote dimer formation, most surface Notch molecules in mammalian cells are monomeric as are constitutively active or inactive Notch1 Proteins. Using a bacterial assay for TM dimerization, we find that the isolated TMD of Notch and amyloid precursor protein self-associate and that mutations affecting Notch cleavage by γ-secretase cleavage do not alter TMD dimerization. Our results indicate that ligand-induced reversal of controlled TMD dimerization by the Notch extracellular domain is unlikely to underlie the regulatory mechanism of intramembranous cleavage.
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Murine Notch homologs (N1-4) undergo presenilin-dependent proteolysis.
Journal of Biological Chemistry, 2001Co-Authors: Meera T. Saxena, Eric H. Schroeter, Jeff S. Mumm, Raphael KopanAbstract:Oncogenic forms of Notch1, Notch2, and Notch4 appear to mimic signaling intermediates of Notch1 and suggest that the role of proteolysis in Notch signaling has been conserved. Here we demonstrate that extracellularly truncated Notch homologs are substrates for a presenilin-dependent gamma-secretase activity. Despite minimal conservation within the transmembrane domain, the requirement for a specific amino acid (P1' valine) and its position at the cleavage site relative to the cytosolic border of the transmembrane domain are preserved. Cleaved, untethered Notch intracellular domains from each receptor translocate to the nucleus and interact with the transcriptional regulatory protein CSL. All four Notch Proteins display presenilin-dependent transactivating potential on a minimal promoter reporter. Thus, this study increases the number of biochemically characterized gamma-secretase substrates from two to five. Despite a high degree of structural homology and the presenilin-dependent activity of truncated Notch Proteins, the extent that this reflects functional redundancy is unknown.
Iva Greenwald - One of the best experts on this subject based on the ideXlab platform.
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Evidence for functional redundancy between C. elegans ADAM Proteins SUP-17/Kuzbanian and ADM-4/TACE
Developmental Biology, 2005Co-Authors: Sophie Jarriault, Iva GreenwaldAbstract:Abstract The ectodomain of LIN-12/Notch Proteins is cleaved and shed upon ligand binding. In Caenorhabditis elegans, genetic evidence has implicated SUP-17, the ortholog of Drosophila Kuzbanian and mammalian ADAM10, as the protease that mediates this event. In mammals, however, biochemical evidence has implicated TACE, a different ADAM protein. We have investigated potential functional redundancy of sup-17 and the C. elegans ortholog of TACE, adm-4, by exploring their roles in cell fate decisions mediated by lin-12/Notch genes. We found that reduced adm-4 activity, like reduced sup-17 activity, suppresses an allele of glp-1 that encodes a constitutively active receptor. Furthermore, concomitant reduction of adm-4 and sup-17 activity causes the production of two anchor cells in the hermaphrodite gonad, instead of one—a phenotype associated with loss of lin-12 activity. Concomitant reduction of both sup-17 and adm-4 activity in hermaphrodites results in highly penetrant synthetic sterility, which appears to reflect a defect in the spermatheca. Expression of a truncated form of LIN-12 that mimics the product of ectodomain shedding rescues this fertility defect, suggesting that sup-17 and adm-4 may mediate ectodomain shedding of LIN-12 and/or GLP-1. Our results are consistent with the possibility that sup-17 and adm-4 are functionally redundant for at least a subset of LIN-12/Notch-mediated decisions in C. elegans.
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LIN-12/Notch signaling in C. elegans.
WormBook, 2005Co-Authors: Iva GreenwaldAbstract:Receptors of the LIN-12/Notch family mediate cell-cell interactions during animal development, and aberrations in LIN-12/Notch signaling have been implicated in human disease. Studies in C. elegans have been instrumental in defining the basic features of the LIN-12/Notch pathway, the role of LIN-12/Notch Proteins as receptors for intercellular signals, the mechanism of signal transduction, and the regulation of LIN-12/Notch signaling during cell fate decisions. This chapter is focused on detailing how the "awesome power of C. elegans genetics" has identified many core components and modulators of LIN-12/Notch activity.
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chapter 256 induction and lateral specification mediated by lin 12 Notch Proteins
Handbook of Cell Signaling, 2003Co-Authors: Sophie Jarriault, Iva GreenwaldAbstract:Receptors of the LIN-12/Notch family are evolutionarily conserved single pass transmembrane Proteins. A single Notch gene exists in Drosophila, whereas two, tin-12 and glp-1, have been described in C elegans and four, Notch-1 to Notch-4, in vertebrates. The ligands for LIN-12/Notch are single pass transmembrane Proteins of the DSL family, after canonical Proteins from Drosophila and C elegans (Lag-2). Genetic and biochemical experiments on invertebrates, mainly C. elegans and Drosophila melanogaster, and more recently on vertebrates, have defined members of the LIN-12/ Notch signal transduction pathway, as well as an original model for signal transduction. This chapter describes general and conserved features of the LIN-12/Notch signal transduction pathway. It also describes features of two different binary cell fate decisions mediated by this pathway in Caenorhabditis elegans. Finally, it discusses whether the primary role of Notch is to mediate binary decisions between alternative cell fates or to block differentiation.
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Handbook of Cell Signaling - CHAPTER 256 – Induction and Lateral Specification Mediated by LIN-12/Notch Proteins
Handbook of Cell Signaling, 2003Co-Authors: Sophie Jarriault, Iva GreenwaldAbstract:Receptors of the LIN-12/Notch family are evolutionarily conserved single pass transmembrane Proteins. A single Notch gene exists in Drosophila, whereas two, tin-12 and glp-1, have been described in C elegans and four, Notch-1 to Notch-4, in vertebrates. The ligands for LIN-12/Notch are single pass transmembrane Proteins of the DSL family, after canonical Proteins from Drosophila and C elegans (Lag-2). Genetic and biochemical experiments on invertebrates, mainly C. elegans and Drosophila melanogaster, and more recently on vertebrates, have defined members of the LIN-12/ Notch signal transduction pathway, as well as an original model for signal transduction. This chapter describes general and conserved features of the LIN-12/Notch signal transduction pathway. It also describes features of two different binary cell fate decisions mediated by this pathway in Caenorhabditis elegans. Finally, it discusses whether the primary role of Notch is to mediate binary decisions between alternative cell fates or to block differentiation.
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LIN-12/Notch signaling: lessons from worms and flies
Genes & Development, 1998Co-Authors: Iva GreenwaldAbstract:LIN-12/Notch Proteins function as receptors for intercellular signals during development. Many aspects of LIN-12/Notch-mediated signaling have been elucidated through studies of cell–cell interactions that occur during Caenorhabditis elegans and Drosophila melanogaster development. The basic principles that operate in these lower organisms have also been shown to apply to vertebrates (for review, see Gridley 1997). Molecular features defined in lower organisms have also been shown to be conserved in vertebrates, including components of the signaling and signal transduction systems (for review, see Weinmaster 1997). The focus of this paper is on what has been learned about LIN-12/Notch signaling from invertebrates. First, a description of roles for LIN12/Notch Proteins in development is given, using different model cell fate decisions to illustrate various features. A discussion of the mechanism of LIN-12/Notch signal transduction follows, including new in vivo evidence that favors the direct participation of the intracellular domain of LIN-12/Notch Proteins in regulating target gene expression. Finally, other influences on LIN-12/ Notch activity are discussed, particularly protein turnover and protein processing.
Freddy Radtke - One of the best experts on this subject based on the ideXlab platform.
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Paradigms of Notch Signaling in Mammals
International Journal of Hematology, 2005Co-Authors: Alexis Dumortier, H. Robson Macdonald, Anne Wilson, Freddy RadtkeAbstract:Notch Proteins regulate a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal life. These Proteins are involved in organogenesis during embryonic development as well as in the maintenance of homeostasis of self-renewing systems. The paradigms of Notch function, such as stem and progenitor cell maintenance, lineage specification mediated by binary cell fate decisions, and induction of terminal differentiation, were initially established in invertebrates and subsequently confirmed in mammals. Moreover, aberrant Notch signaling is linked to tumorigenesis. In this review, we discuss the origin of postulated Notch functions, give examples from different mammalian organ systems, and try to relate them to the hematopoietic system.
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Notch regulation of lymphocyte development and function
Nature Immunology, 2004Co-Authors: Freddy Radtke, Anne Wilson, Stephane J C Mancini, Robson H MacdonaldAbstract:Notch Proteins regulate a broad spectrum of cell fate decisions and differentiation processes during fetal and postnatal development. Mammals have four Notch receptors that bind five different ligands. The function of Notch signaling during lymphopoiesis and T cell neoplasia, based on gain-of-function and conditional loss-of-function approaches for the Notch1 receptor, indicates Notch1 is essential in T cell lineage commitment. Recent studies have addressed the involvement of other Notch receptors and ligands as well as their downstream targets, demonstrating additional functions of Notch signaling in embryonic hematopoiesis, intrathymic T cell development, B cell development and peripheral T cell function.
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inactivation of Notch1 in immature thymocytes does not perturb cd4 or cd8 t cell development
Nature Immunology, 2001Co-Authors: Anita Wolfer, Anne Wilson, Robson H Macdonald, Talitha R Bakker, Michael Nicolas, Vassilios Ioannidis, Dan R Littman, Christopher B Wilson, Werner Held, Freddy RadtkeAbstract:Notch Proteins influence cell-fate decisions in many developing systems. Several gain-of-function studies have suggested a critical role for Notch 1 signaling in CD4-CD8 lineage commitment, maturation and survival in the thymus. However, we show here that tissue-specific inactivation of the gene encoding Notch 1 in immature (CD25+CD44-)T cell precursors does not affect subsequent thymocyte development. Neither steady-state numbers nor the rate of production of CD4+ and CD8+ mature thymocytes is perturbed in the absence of Notch 1. In addition, Notch 1-deficient thymocytes are normally sensitive to spontaneous or glucocorticoid-induced apoptosis. In contrast to earlier reports, these data formally exclude an essential role for Notch 1 in CD4-CD8 lineage commitment, maturation or survival.
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Notch1 and T-cell development: insights from conditional knockout mice.
Trends in Immunology, 2001Co-Authors: H. Robson Macdonald, Anne Wilson, Freddy RadtkeAbstract:Notch Proteins influence cell-fate decisions in many developmental systems. Gain-of-function studies have suggested a crucial role for Notch1 signaling at several stages during lymphocyte development, including the B/T, alphabeta/gammadelta and CD4/CD8 lineage choices. Here, we critically re-evaluate these conclusions in the light of recent studies that describe inducible and tissue-specific targeting of the Notch1 gene.
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deficient t cell fate specification in mice with an induced inactivation of Notch1
Immunity, 1999Co-Authors: Freddy Radtke, Anne Wilson, Robson H Macdonald, G Stark, Michelle Bauer, Joost P M Van Meerwijk, Michel AguetAbstract:Notch Proteins are cell surface receptors that mediate developmental cell specification events. To explore the function of murine Notch1, an essential portion of the gene was flanked with loxP sites and inactivation induced via interferon-regulated Cre recombinase. Mice with a neonatally induced loss of Notch1 function were transiently growth retarded and had a severe deficiency in thymocyte development. Competitive repopulation of lethally irradiated wild-type hosts with wild-type- and Notch1-deficient bone marrow revealed a cell autonomous blockage in T cell development at an early stage, before expression of T cell lineage markers. Notch1-deficient bone marrow did, however, contribute normally to all other hematopoietic lineages. These findings suggest that Notch1 plays an obligatory and selective role in T cell lineage induction.
Karim Malik - One of the best experts on this subject based on the ideXlab platform.
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A Wnt-BMP4 Signaling Axis Induces MSX and Notch Proteins and Promotes Growth Suppression and Differentiation in Neuroblastoma.
Cells, 2020Co-Authors: Marianna Szemes, Zsombor Melegh, Jacob Bellamy, Madhusudhan Kollareddy, Daniel Catchpoole, Alexander Greenhough, Karim MalikAbstract:The Wnt and bone morphogenetic protein (BMP) signaling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumor arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/β-catenin signaling can have cell-type-specific effects on neuroblastoma phenotypes, including growth inhibition and differentiation, and that BMP4 mRNA and protein were induced by Wnt3a/Rspo2. In this study, we characterised the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signaling and BMP4-induced growth suppression and differentiation. An immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumors, in contrast to a high expression in ganglion cells. These results are consistent with a tumor suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signaling, verified by increases of Notch3 and Hes1 Proteins. Together, our data demonstrate, for the first time, Wnt-BMP-Notch signaling crosstalk associated with growth suppression of neuroblastoma.
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A Wnt-BMP4 signalling axis induces MSX and Notch Proteins and promotes growth suppression and differentiation in neuroblastoma
2020Co-Authors: Marianna Szemes, Zsombor Melegh, Jacob Bellamy, Madhusudhan Kollareddy, Daniel Catchpoole, Karim MalikAbstract:The Wnt and bone morphogenetic protein (BMP) signalling pathways are known to be crucial in the development of neural crest lineages, including the sympathetic nervous system. Surprisingly, their role in paediatric neuroblastoma, the prototypic tumour arising from this lineage, remains relatively uncharacterised. We previously demonstrated that Wnt/{beta}-catenin signalling can have cell-type specific effects on neuroblastoma phenotypes, including growth inhibition and differentiation, and that BMP4 mRNA and protein were induced by Wnt3a/Rspo2. In this study, we characterise the phenotypic effects of BMP4 on neuroblastoma cells, demonstrating convergent induction of MSX homeobox transcription factors by Wnt and BMP4 signalling and BMP4-induced growth suppression and differentiation. Immunohistochemical analysis of BMP4 expression in primary neuroblastomas confirms a striking absence of BMP4 in poorly differentiated tumours, in contrast to high expression in ganglion cells. These results are consistent with a tumour suppressive role for BMP4 in neuroblastoma. RNA sequencing following BMP4 treatment revealed induction of Notch signalling, verified by increases of Notch3 and Hes1 Proteins. Together, our data demonstrate for the first time Wnt-BMP-Notch signalling crosstalk associated with growth suppression of neuroblastoma.
