SEARCH · PubMed Health

Results for “Receptor, Notch2”

Explore indexed PubMed citations for clinical trials, systematic reviews and public health research. Read source abstracts and follow each citation to its original PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 181 records · Page 10Linked to original sources

PubMed2005

Immunohistological localization of Notch receptors and their ligands Delta and Jagged in synovial tissues of rheumatoid arthritis.

BACKGROUND: The interaction of Notch receptors with their transmembrane ligands Delta and Jagged plays an important role not only in the organization of a variety of tissues but also in several genetic disorders and cancer development. The functional involvement of the Notch signaling in rheumatoid arthritis (RA) has been reported previously, but the expression profile of Notch-related molecules, as well as their relation with clinicopathological parameters, remains unclear. METHODS: In this study, we analyzed the immunohistochemical staining pattern of four Notch receptors (Notch1-4) and their ligands (Delta1 and Jagged1) in 14 synovial tissues obtained from 14 RA patients. RESULTS: Notch2 and Notch4 were expressed in limited areas in a few samples or in small blood vessels, respectively. Notch1, Notch3, Delta1, and Jagged1 were overexpressed in the synovial lining and sublining cells on synovial hyperplastic lesions in all samples. Notch1 expression was also observed in T and B lymphocytes of lymphoid follicles independently. Notch1 and Notch3 expression overlapped with that of Jagged1, as determined by confocal microscopy. Activation of Notch1 signaling in the RA synovium was identified using a specific antibody to the cleaved form of Notch1. The expression of these molecules did not show any correlation with clinicopathological parameters. CONCLUSIONS: Our results suggest that Notch signaling is activated in RA synovium but does not necessarily reflect the pathological condition of RA.

Adolescent↗

PubMed1998

Delta-notch signaling in odontogenesis: correlation with cytodifferentiation and evidence for feedback regulation.

Recent data suggest that dental cells utilize the evolutonarily conserved Notch-mediated intercellular signaling pathway to regulate their fates. Here we report on the expression and regulation of Delta1, a transmembrane ligand of the Notch receptors, during mouse odontogenesis. Delta1 is weakly expressed in dental epithelium during tooth initiation and morphogenesis, but during cytodifferentiation, expression is upregulated in the epithelium-derived ameloblasts and the mesenchyme-derived odontoblasts. The expression pattern of Delta1 in ameloblasts and odontoblasts is complementary to Notch1, Notch2, and Notch3 expression in adjacent epithelial and mesenchymal cells. Notch1 and Notch2 are upregulated in explants of dental mesenchyme adjacent to implanted cells expressing Delta1, suggesting that feedback regulation by Delta-Notch signaling ensures the spatial segregation of Notch receptors and ligands. TGFbeta1 and BMPs induce Delta1 expression in dental mesenchyme explants at the stage at which Delta1 is upregulated in vivo, but not at earlier stages. In contrast to the Notch family receptors and their ligand Jagged1, expression of Delta1 in the tooth germ is not affected by epithelial-mesenchymal interactions, showing that the Notch receptors and their two ligands Jagged1 and Delta1 are subject to different regulations.

Animals↗

PubMed2001

Notch pathway genes are expressed in mammalian ovarian follicles.

Folliculogenesis is the process of development of ovarian follicles that ultimately results in the release of fertilizable oocytes at ovulation. This is a complex program that involves the proliferation and differentiation of granulosa cells. Granulosa cells are necessary for follicle growth and support the oocyte during folliculogenesis. Genes that regulate the proliferation and differentiation of granulosa cells are beginning to be elucidated. In this study, the expression patterns of Notch receptor genes and their ligands, which have been shown to regulate cell-fate decisions in many systems during development, were examined in the mammalian ovary. In situ hybridization data showed that Notch2, Notch3, and Jagged2 were expressed in an overlapping pattern in the granulosa cells of developing follicles. Jagged1 was expressed in oocytes exclusively. Downstream target genes of Notch also were expressed in granulosa cells. These data implicate the Notch signaling pathway in the regulation of mammalian folliculogenesis.

Animals↗

PubMed2000

Localisation of members of the notch system and the differentiation of vibrissa hair follicles: receptors, ligands, and fringe modulators.

Hair vibrissa follicle morphogenesis involves several cell segregation phases, in the dermis as well as in the epidermis. The expression of Notch-related genes, which are well established mediators of multiple cell segregation events in Drosophila development, was studied by in situ hybridisation during embryonic mouse vibrissa follicle morphogenesis and the first adult hair cycle. The results show that two receptors, Notch1 and -2, three ligands, Delta1, Serrate1, and -2, and the three Fringe regulators, Lunatic, Manic, and Radical, are expressed in different locations and morphogenetic stages. First, the appearance of hair vibrissa primordia involves the expression of complementary patterns of Notch2, Delta1, and Lunatic Fringe in the dermis and of Notch1, Serrate2, and Lunatic Fringe in the epidermis. Second, this expression pattern is no longer found after stage 3 in the dermis. Meanwhile, in the epidermis, the expression of Notch1, Serrate2, and Lunatic Fringe before the formation of the placode may be involved in determining two populations of epidermal cells in the developing follicle. Third, complementary expression patterns for Notch1, Manic, and Lunatic Fringe, as well as Serrate1 and -2 as previously shown (Powell et al., 1998), are progressively established from stage 4 of embryonic development both in the outer root sheath and in the hair matrix. These patterns are consistent with the one found in the adult anagen phase. During the hair vibrissa cycle, Notch1 and Manic Fringe display temporal and spatial changes of expression, suggesting that they may intervene as modulators of trichocyte activities.

Animals↗

PubMed2003

Notch activation suppresses fibroblast growth factor-dependent cellular transformation.

Aberrant activations of the Notch and fibroblast growth factor receptor (FGFR) signaling pathways have been correlated with neoplastic growth in humans and other mammals. Here we report that the suppression of Notch signaling in NIH 3T3 cells by the expression of either the extracellular domain of the Notch ligand Jagged1 or dominant-negative forms of Notch1 and Notch2 results in the appearance of an exaggerated fibroblast growth factor (FGF)-dependent transformed phenotype characterized by anchorage-independent growth in soft agar. Anchorage-independent growth exhibited by Notch-repressed NIH 3T3 cells may result from prolonged FGFR stimulation caused by both an increase in the expression of prototypic and oncogenic FGF gene family members and the nonclassical export of FGF1 into the extracellular compartment. Interestingly, FGF exerts a negative effect on Notch by suppressing CSL (CBF-1/RBP-Jk/KBF2 in mammals, Su(H) in Drosophila and Xenopus, and Lag-2 in Caenorhabditis elegans)-dependent transcription, and the ectopic expression of constitutively active forms of Notch1 or Notch2 abrogates FGF1 release and the phenotypic effects of FGFR stimulation. These data suggest that communication between the Notch and FGFR pathways may represent an important reciprocal autoregulatory mechanism for the regulation of normal cell growth.

3T3 Cells↗

PubMed2003

Notch-associated gene expression in embryonic and adult taste papillae and taste buds suggests a role in taste cell lineage decisions.

The Notch signaling pathway is involved in cell fate decisions during development. To explore the role of this signaling cascade in the taste system, we investigated the expression patterns of Notch signaling genes in fetal and adult mouse tongues using in situ hybridization. Three of the four murine Notch receptors, their ligands, Delta-like 1 (Dll-1), Jagged1, and Jagged2, as well as three transcription factors, Hes1, Hes6, and Mash1, are expressed in the embryonic taste epithelium. Expression is first detected in the circumvallate papilla at embryonic day E14.5, when Notch1, Jagged1, and Jagged2 are expressed broadly in the papilla and general lingual epithelium. In contrast, Mash1 and Hes6 are restricted to only a few epithelial cells in the apical region of the developing papilla. By E18.5, many of the genes now exhibit a bimodal expression pattern in the papillary epithelium: apically and dorsally they are expressed in sparse clusters of cells, while more ventrally expression typically occurs throughout the lower regions of the trenches. The extent of papilla innervation was compared with Mash1 and Hes6 expression. At E14.5, when Hes6 and Mash1 are already expressed in small numbers of epithelial cells, PGP9.5 immunoreactive fibers have not yet invaded the epithelium, consistent with the specification of taste bud primordia prior to nerve contact. All of the genes examined (except Notch2) are also expressed in subsets of cells within circumvallate taste buds in adult mice, although Notch1 is restricted to basal cells adjacent to taste buds. The onset of embryonic Notch associated gene expression after the morphological differentiation of the circumvallate papilla argues that this signaling cascade may specify taste receptor cell lineages within an already specified taste papilla. Similarly, Notch gene expression in adult taste buds suggests continued roles in cell lineage determination and cell turnover.

Animals↗

PubMed2004

Notch expression in developing olfactory neuroepithelium.

Notch genes encode receptors for signaling pathways that regulate neurogenesis in various tissues. To better understand the roles of Notch genes in olfactory neurogenesis, we studied the expression of Notch family in developing mouse olfactory epithelium. In the earliest stage of olfactory development, Notch1 was observed in the mesenchyme lateral to the olfactory placode. During the developmental stage, Notch1 was mainly observed around the basal membrane, while Notch3 was observed in the lower compartment of the olfactory neuroepithelium. Notch2 was not detected during the entire observation period. As the olfactory neuroepithelium grew mature, both Notch1 and Notch3 gradually disappeared. These results suggest distinct roles of Notch1 and Notch3 in the neurogenesis of the peripheral olfactory system.

Animals↗

PubMed2006

Expression of Notch and Wnt pathway components and activation of Notch signaling in medulloblastomas from heterozygous patched mice.

Hedgehog (Hh), Notch, and Wingless (Wnt) signaling control normal development of the cerebellum, and dysregulation of these signaling pathways are associated with medulloblastoma (MB). As an initial step in the study of the role of interacting signaling pathways in MB pathogenesis, we demonstrate the expression of several components of the Notch and Wnt signaling pathways, and activation of Notch signaling in MB from Ptch +/- mice that have elevated Hh signaling. We also show a marked downregulation in the expression of Notch2, Jagged1, Hes1, mSfrp1, and mFrz7 in cerebella of developing mice with reduced Hh signaling, suggesting that Hh signaling regulates the expression of these genes. Together with recent published data, these findings indicate that Hh signaling might synergize simultaneously with Notch and Wnt signaling in MB development by controlling Notch and Wnt pathway ligand, receptor and/or target gene expression.

Animals↗

PubMed2005

Amyloid precursor protein interacts with notch receptors.

The amyloid precursor protein (APP) must fulfill important roles based on its sequence conservation from fly to human. Although multiple functions for APP have been proposed, the best-known role for this protein is as the precursor of Abeta peptide, a neurotoxic 39-43-amino acid peptide crucial to the pathogenesis of Alzheimer's disease. To investigate additional roles for APP with an eye toward understanding the molecular basis of the pleiotropic effects ascribed to APP, we isolated proteins that interacted with the plasma membrane isoform of APP. We employed a membrane-impermeable crosslinker to immobilize proteins binding to transmembrane APP in human embryonic kidney (HEK)293 cells expressing APP751 (HEK275) or rat embryonic day 18 primary neurons infected with a virus expressing APP. Notch2 was identified as a potential APP binding partner based on mass spectrometry analysis of APP complexes immunopurified from neurons. To confirm the interaction between Notch2 and APP, we carried out immunoprecipitation studies in HEK275 cells transiently expressing full-length Notch2 using Notch2 antibodies. The results indicated that APP and Notch2 interact in mammalian cells, and confirmed our initial findings. Interestingly, Notch1 also coimmunoprecipitated with APP, suggesting that APP and Notch family members may engage in intermolecular cross talk to modulate cell function. Finally, cotransfection of APP/CFP and Notch2/YFP into COS cells revealed that these two proteins colocalize on the plasma membrane. Intracellularly, however, although some APP and Notch molecules colocalize, others reside in distinct locations. The discovery of proteins that interact with APP may aid in the identification of new functions for APP.

Amyloid beta-Protein Precursor↗

PubMed2004

A novel notch protein, N2N, targeted by neutrophil elastase and implicated in hereditary neutropenia.

Mutations in ELA2, encoding the human serine protease neutrophil elastase, cause cyclic and severe congenital neutropenia, and recent evidence indicates that the mutations alter the membrane trafficking of neutrophil elastase. These disorders feature impaired bone marrow production of neutrophils along with excess monocytes-terminally differentiated lineages corresponding to the two alternative fates of myeloid progenitor cells. We utilized a modified yeast two-hybrid system and identified a new, widely expressed gene, N2N, whose product is homologous to Notch2, that interacts with neutrophil elastase. N2N is a 36-kDa protein distributed throughout the cell and secreted. Its amino-terminal sequence consists of several EGF repeats identical to those of the extracellular region of Notch2, and its carboxyl terminus contains a unique 24-residue domain required for interaction with neutrophil elastase. Neutrophil elastase cleaves N2N within EGF repeats in vitro and in living cells, but the C-terminal domain retards proteolysis. In vitro, N2N represses transcriptional activities of Notch proteins. Disease-causing mutations of neutrophil elastase disrupt the interaction with N2N, impair proteolysis of N2N and Notch2, and interfere with Notch2 signaling, suggesting defective proteolysis of an inhibitory form of Notch as an explanation for the alternate switching of cell fates characteristic of hereditary neutropenia.

Cloning, Molecular↗

PubMed2007

Effects of sulfated hyaluronan on keratinocyte differentiation and Wnt and Notch gene expression.

Sulfated hyaluronan (SHya), which is composed of a sulfated group and hyaluronan (Hya), has high activity on and biocompatibility with cells. When normal human epidermal keratinocytes (NHEKs) were incubated in dishes coated with SHya, cell proliferation was suppressed in a dose-dependent manner. The expression levels of keratin 1 and loricrin mRNAs, as detected by real-time RT-PCR, were increased significantly. The expressions of Wnt mRNAs, which play important roles in cell proliferation and differentiation, were modulated. Wnt4 and Wnt6 mRNA expressions were increased compared to controls, while expression of Wnt5a was similar to the control and that of Wnt7a mRNA was decreased. In addition, the expression of Notch mRNAs, which play a critical role in keratinocyte differentiation, were affected. Notch3 mRNA was increased significantly, while Notch1 mRNA was decreased compared to controls, and expression of Notch2 was similar to that of control. These results suggested that a SHya-coated scaffold might be useful for regulating cell activity in tissue engineering.

Cell Differentiation↗

PubMed2001

Murine notch homologs (N1-4) undergo presenilin-dependent proteolysis.

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.

Amino Acid Sequence↗

PubMed2004

Notch signaling in lymphocyte development and function.

Over the past few years, the crucial role of Notch signaling in multiple stages of T-cell development has become apparent. Recent studies have helped to define more precisely the functions and components of the Notch signaling pathway in T-cell development, including during the T versus B fate decision and in early CD4(-)CD8(-)double-negative thymocytes. In addition, new evidence points to a requirement for Notch2 in the development of marginal zone B cells. Finally, recent studies have provided our first glimpse into the complex and paradoxical roles of Notch signaling in the activation and differentiation of mature T cells.

Animals↗

PubMed2001

Notch signaling in leukemia.

Mammalian Notch homologs were first identified from the involvement of Notch1 in a recurrent chromosomal translocation in a subset of human T-cell leukemias. The effect of the translocation was twofold: Notch expression was placed under the control of a T-cell-specific element, and Notch was truncated, resulting in a constitutively active protein. Subsequent work has shown that Notch1 is required for T cell commitment and is exclusively oncotropic for T cells. During the past year, several murine models have been used to dissect the function of Notch signaling in lymphoid development and leukemia. These models show that Notch1 drives the earliest stages of T cell commitment and that Notch signaling must be downregulated by the double positive stage for proper T cell development to occur. Constitutive Notch signaling mediated by Notch1, Notch2, or Notch3 predisposes to T-cell leukemia. Future studies are expected to elucidate the mechanisms by which Notch leads to transformation. Identification of the transcriptional targets of Notch signaling is likely to yield important insights.

Animals↗

PubMed1997

Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation.

We isolated a novel bHLH protein gene Mesp2 (for mesoderm posterior 2) that cross-hybridizes with Mesp1 expressed in the early mouse mesoderm. Mesp2 is expressed in the rostral presomitic mesoderm, but down-regulated immediately after the formation of the segmented somites. To determine the function of MesP2 protein (MesP2) in somitogenesis, we generated Mesp2-deficient mice by gene targeting. The homozygous Mesp2 (-/-) mice died shortly after birth and had fused vertebral columns and dorsal root ganglia, with impaired sclerotomal polarity. The earliest defect in the homozygous embryos was a lack of segmented somites. Their disruption of the metameric features, altered expression of Mox-1, Pax-1, and Dll1, and lack of expression of Notch1, Notch2, and FGFR1 suggested that MesP2 controls sclerotomal polarity by regulating the signaling systems mediated by notch-delta and FGF, which are essential for segmentation.

Amino Acid Sequence↗

PubMed2000

The Translocon-Associated Protein beta (TRAPbeta) in zebrafish embryogenesis. I. Enhanced expression of transcripts in notochord and hatching gland precursors.

The normal translocation of nascent polypeptides into the lumen of the endoplasmic reticulum (ER) is thought to be aided in part by a translocon-associated protein (TRAP) complex consisting of 4 protein subunits. The association of mature proteins with the ER and Golgi, or other intracellular locales, such as lysosomes, depends on the initial targeting of the nascent polypeptide to the ER membrane. A similar scenario must also exist for proteins destined for secretion. We have identified a member of the TRAP complex using a two hybrid screen to isolate proteins that bind to zebrafish (Danio) Ran binding protein 1. The polypeptide predicted from the largest open reading frame contains 183 amino acids with a 86 and 87% sequence identity to the TRAPbeta subunits in human and chicken, respectively. Sequence analysis identified a cleavable amino-terminal signal peptide in the zebrafish TRAPbeta subunit and a region of the protein spans the membrane of the endoplasmic reticulum. A reverse transcriptase-polymerase chain reaction assay showed that TRAPbeta mRNA is expressed in the developing zebrafish embryo. TRAPbeta mRNA is maternally supplied to the egg and is expressed constitutively throughout development and in the adult. This pattern of expression indicates that the message encoding part of the machinery targeting nascent polypeptides to the ER lumen is available at the onset of embryogenesis when the rate of translation increases exponentially over that occurring in the oocyte. In situ hybridization was used to test whether or not TRAPbeta transcripts might become localized and/or enriched in the developing embryo. Homogeneous staining is seen in the blastula and early gastrula stages. At mid-to-late gastrula stages, however, the message becomes enriched in the developing notochord and polster, or hatching gland rudiment. The TRAPbeta gene, mapped using the LN54 mouse-zebrafish radiation hybrid panel to linkage group 19, resides next to a gene (Z15451) which has sequence homology to notch2 and vascular endothelial growth factor. TRAPbeta, however, does not appear to belong to a group of genes which are syntenic with orthologues or paralogues on human chromosomes.

Amino Acid Sequence↗

PubMed2004

A dual role for Ikk alpha in tooth development.

IKK alpha is a component of the I kappa B kinase (IKK) complex that plays a key role in the activation of NF-kappa B. In Ikk alpha mutant mice and mice expressing a transdominant negative mutant of I kappa B alpha (cI kappa B alpha Delta N), molars have abnormal cusps, indicating that Ikk alpha is involved in cusp formation through the NF-kappa B pathway. However, Ikk alpha mutant incisors also have an earlier phenotype where epithelium evaginates outward into the developing oral cavity rather than invaginating into the underlying mesenchyme. A similar evagination of epithelium was also observed in whisker development, suggesting that Ikk alpha contributes to the direction of epithelial growth during the early stages of development in many ectodermal appendages. Since cI kappa B alpha Delta N mice have normal incisor epithelial invagination, Ikk alpha's role appears to be NF-kappa B independent. Changes in Notch1, Notch2, Wnt7b, and Shh expression found in incisor epithelium of Ikk alpha mutants suggest that this NF-kappa B-independent function is mediated by Notch/Wnt/Shh signaling pathways.

Animals↗

PubMed2005

Functional redundancy of the Notch gene family during mouse embryogenesis: analysis of Notch gene expression in Notch3-deficient mice.

The Notch3 gene, a member of the Notch gene family, is expressed in a wide variety of tissues during development. We generated and analyzed Notch3-deficient mice to assess the in vivo role of the Notch3 gene. Consistent with previous observation of Krebs et al. [Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation, Genesis 37 (3) (2003) 139-143], the Notch3-/- mice were viable, fertile, and developed normally despite abundant expression of Notch3 in various embryonic tissues. We examined the details of Notch1, 2, and 4 expressions in the Notch3-/- embryos compared with those in wild-type embryos. As a result, we found that a deficiency in Notch3 did not affect the expression of Notch1, 2, and 4, and that either Notch1 or Notch2, or sometimes both, was always expressed in all Notch3-expressing tissues examined. These results support the idea that other Notch genes functionally compensate for Notch3 during embryonic development. We also surveyed the adult tissues of Notch3-/- mice and found significantly fewer thymocytes in 10-week-old mice. Therefore, the thymus might be a target tissue affected by Notch3 deficiency.

Animals↗