Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Notch pathway”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

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

At least 109 records · Page 6Linked to original sources
PubMed1999

Rel/NF-kappaB can trigger the Notch signaling pathway by inducing the expression of Jagged1, a ligand for Notch receptors.

Jagged1 belongs to the DSL family of ligands for Notch receptors that control the proliferation and differentiation of various cell lineages. However, little is known about the transcription factors that regulate its expression. Here, we show that Jagged1 is a Rel/NF-kappaB-responsive gene. Both c-Rel and RelA induced jagged1 gene expression, whereas a mutant defective for transactivation did not. Importantly, jagged1 transcripts were also upregulated by endogenous NF-kappaB activation and this effect was inhibited by a dominant mutant of IkappaBalpha, a physiological inhibitor of NF-kappaB. Cell surface expression of Jagged1 in c-Rel-expressing cell monolayers led to a functional interaction with lymphocytes expressing the Notch1/TAN-1 receptor. This correlated with the initiation of signaling downstream of Notch, as evidenced by increased levels of HES-1 transcripts in co-cultivated T cells and of CD23 transcripts in co-cultivated B cells. Consistent with its Rel/NF-kappaB-dependent induction, Jagged1 was found to be highly expressed in splenic B cells where c-Rel is expressed constitutively. These results demonstrate that c-Rel can trigger the Notch signaling pathway in neighboring cells by inducing jagged1 gene expression, and suggest a role for Jagged1 in B-cell activation, differentiation or function. These findings also highlight the potential for an interplay between the Notch and NF-kappaB signaling pathways in the immune system.

B-Lymphocytes↗
PubMed2004

Developmental expression of the Notch signaling pathway genes during mouse preimplantation development.

Notch signaling is an evolutionary conserved pathway involved in intercellular signaling and essential for proper cell fate choices during development. Thus, it could be involved in mouse preimplantation development where intercellular signaling plays a crucial role, particularly between the inner cell mass and the trophectoderm of the blastocyst. At their face value, the phenotypes observed when disrupting each of the four Notch genes known in the mouse do not support this view as none of them involves perturbation of preimplantation development. However this could be due to functional redundancy and/or maternal expression. As a first step to address this issue, we decided to examine the expression in early development of various genes known to participate in Notch signaling. Here, we report on the expression pattern of Notch1-4, Jagged1 (Jag1), Jag2, Delta-like1 (Dll-1), Dll-3, Dll-4, Rbpsuh, Deltex1(Dtx1)and Dtx2 genes during preimplantation development from unfertilized eggs until late blastocyst stage using a RT-PCR strategy. We show that Notch1, 2, Jag1-2, Dll-3, Rbpsuh and Dtx2 transcripts are expressed at all stages. Notch4 and Dll-4 mRNAs are synthesized from the 2-cell through to the hatched blastocyst stage. Notch3, Dll-1 and Dtx1exhibit a stage dependent expression as their mRNAs are detected in 2-cell embryos and in hatched blastocysts, but are absent or weakly detected at the morula stage. Finally, we show that all the above genes are expressed both in Embryonic and Trophoblast Stem cells (ES and TS cells, respectively). Our results suggest that the Notch pathway may be active during mouse preimplantation development.

Animals↗
PubMed2002

Notching up another pathway.

The Notch proteins play a vital role in cell fate decisions in both invertebrate and vertebrate development. Careful analysis of this role has led to a model of signalling downstream of these receptors, via the CSL (CBF1, Suppressor of Hairless, Lag-1) family of transcription factors. There have been suggestions, however, that Notch can signal through other pathways. In the current paper, Ramain et al. provide compelling evidence for Notch signalling through a CSL-independent pathway and they demonstrate that the cytoplasmic protein, Deltex, is required for this signal. In addition, they show that Wnt signalling may regulate this Deltex-dependent signal.

Alleles↗
PubMed1995

Hairless promotes stable commitment to the sensory organ precursor cell fate by negatively regulating the activity of the Notch signaling pathway.

In Drosophila imaginal discs, the function of the Hairless (H) gene is required at multiple steps during the development of adult sensory organs. Here we report the results of a series of experiments designed to investigate the in vivo role of H in sensory organ precursor (SOP) cell specification. We show that the proneural cluster pattern of proneural gene expression and of transcriptional activation by proneural proteins is established normally in the absence of H activity. By contrast, single cells with the high levels of achaete, scabrous, and neuralized expression characteristic of SOPs almost always fail to appear in H mutant proneural clusters. These results indicate that H is required for a relatively late step in the development of the proneural cluster, namely, the stable commitment of a single cell to the SOP cell fate. We also show that expression of an activated form of the Notch receptor leads to bristle loss with the same cellular basis--failure of SOP determination--as loss of H function and that simultaneous overexpression of H suppresses this effect. Finally, we demonstrate by epistasis experiments that the failure of stable commitment to the SOP fate in H null mutants requires the activity of the genes of the Enhancer of split complex, including groucho. Our results indicate that H promotes SOP determination by antagonizing the activity of the Notch pathway in this cell, thereby protecting it from inhibitory signaling by its neighbors in the proneural cluster. We propose a simple threshold model in which the principal role of H in SOP specification is to translate a quantitative difference in the activity of the Notch pathway (in the SOP versus the non-SOP cells) into a stable binary cell fate decision.

Animals↗
PubMed2000

Mouse mutant "rib-vertebrae" (rv): a defect in somite polarity.

The recessive mouse mutant rib-vertebrae (rv) affects the morphogenesis of the axial skeleton. The phenotype is characterized by vertebral defects such as fusion of adjacent segments, hemivertebrae, or open neural arches and rib defects including fusions, forked ribs, and additional ribs. We have analyzed this mutant in detail and are able to show that defective somite patterning underlies the vertebral malformations. The rv mutation leads to an elongation of the presomitic mesoderm and a disruption of the anterior-posterior polarization of somites, as indicated by the abnormal expression of Pax1 and Mox1. Somites are irregular in size but the overall formation of somites appears unaffected. These changes are reminiscent of somite defects obtained in loss of function alleles of the Delta-Notch pathway. Expression of the Notch pathway components Delta-like-1 (Dll1) and lunatic fringe (Lfng) are altered in rv mutants. To investigate possible interactions of rv with components of the Notch pathway, we crossed rv into Dll1(lacZ). Double heterozygous (rv/+; Dll1(lacZ)/+) mice show vertebral defects and homozygous animals with one inactive Dll1 allele (rv/rv; Dll1(lacZ)/+) exhibit a dramatic increase in phenotypic severity, indicating that rv and Dll1 genetically interact. We have mapped rv to a region on chromosome 7 that is syntenic to human chromosomes 11p, 10q, and 11p. rv is phenotypically similar to human vertebral malformations syndromes and can serve as a model for these conditions.

Animals↗
PubMed2004

Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway.

Notch signaling is involved in a variety of cell-fate decisions during development. Here we investigate the role of Notch signaling in apoptotic cell death of neural progenitors through the generation and analysis of cell type-specific conditional transgenic and knockout mice. We show that conditional expression of a constitutively active form of Notch1 in early neural progenitor cells, but not postmitotic neurons, selectively induces extensive apoptosis, resulting in a markedly reduced progenitor population. Conversely, attenuation of Notch signaling in Notch1 conditional knockout or Presenilin-1-/- mice results in reduced apoptosis of early neural progenitor cells. Furthermore, Notch activation in neural progenitor cells leads to elevated levels of nuclear p53 and transcriptional upregulation of the target genes Bax and Noxa, and the promotion of apoptotic cell death by Notch activation is completely suppressed by p53 deficiency. Together, these complementary gain-of-function and loss-of-function studies reveal a previously unappreciated role of Notch signaling in the regulation of apoptotic cell death during early mammalian neural development.

Animals↗
PubMed2003

Echinoid mutants exhibit neurogenic phenotypes and show synergistic interactions with the Notch signaling pathway.

During neurogenesis in Drosophila, groups of ectodermal cells are endowed with the capacity to become neuronal precursors. The Notch signaling pathway is required to limit the neuronal potential to a single cell within each group. Loss of genes of the Notch signaling pathway results in a neurogenic phenotype: hyperplasia of the nervous system accompanied by a parallel loss of epidermis. Echinoid (Ed), a cell membrane associated Immunoglobulin C2-type protein, has previously been shown to be a negative regulator of the EGFR pathway during eye and wing vein development. Using in situ hybridization and antibody staining of whole-mount embryos, we show that Ed has a dynamic expression pattern during embryogenesis. Embryonic lethal alleles of ed reveal a role of Ed in restricting neurogenic potential during embryonic neurogenesis, and result in a phenotype similar to that of loss-of-function mutations of Notch signaling pathway genes. In this process Ed interacts closely with the Notch signaling pathway. Loss of ed suppresses the loss of neuronal elements caused by ectopic activation of the Notch signaling pathway. Using a temperature-sensitive allele of ed we show, furthermore, that Ed is required to suppress sensory bristles and for proper wing vein specification during adult development. In these processes also, ed acts in close concert with genes of the Notch signaling pathway. Thus the extra wing vein phenotype of ed is enhanced upon reduction of Delta (Dl) or Enhancer of split [E(spl)] proteins. Overexpression of the membrane-tethered extracellular region of Ed results in a dominant-negative phenotype. This phenotype is suppressed by overexpression of E(spl)m7 and enhanced by overexpression of Dl. Our work establishes a role of Ed during embryonic nervous system development, as well as adult sensory bristle specification and shows that Ed interacts synergistically with the Notch signaling pathway.

Animals↗
PubMed2001

The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway.

We have identified a gene encoding a novel protein that is transcriptionally regulated by the Notch signaling pathway in mammals. This gene, named Nrarp (for Notch-regulated ankyrin-repeat protein), encodes a 114 amino acid protein that has a unique amino-terminus and a carboxy-terminal domain containing two ankyrin-repeat motifs. A Xenopus homolog of the Nrarp gene was previously identified in a large-scale in situ hybridization screen of randomly isolated cDNA clones. We demonstrate that in T-cell and myoblast cell lines expression of the Nrarp gene is induced by the intracellular domain of the Notch1 protein, and that this induction is mediated by a CBF1/Su(H)/Lag-1 (CSL)-dependent pathway. During mouse embryogenesis, the Nrarp gene is expressed in several tissues in which cellular differentiation is regulated by the Notch signaling pathway. Expression of the Nrarp gene is downregulated in Notch1 null mutant mouse embryos, indicating that expression of the Nrarp gene is regulated by the Notch pathway in vivo. Thus, Nrarp transcript levels are regulated by the level of Notch1 signaling in both cultured cell lines and mouse embryos. During somitogenesis, the Nrarp gene is expressed in a pattern that suggests that Nrarp expression may play a role in the formation of somites, and Nrarp expression in the paraxial mesoderm is altered in several Notch pathway mutants that exhibit defects in somite formation. These observations demonstrate that the Nrarp gene is an evolutionarily conserved transcriptional target of the Notch signaling pathway.

Alleles↗
PubMed2004

Role of the Notch signalling pathway in tooth morphogenesis.

Notch receptors are involved in cell fate decisions through the process of lateral inhibition or inductive signalling. Jagged2 belongs to the family of transmembrane proteins that serve as the ligands for Notch receptors. We have analysed the expression of the Jagged2 gene in developing mouse teeth. Jagged2 expression is restricted in inner enamel epithelial cells that give rise to the ameloblasts. We have also examined the role of Jagged2 in tooth development using mutant mice that lack the domain of the Jagged2 protein required for interaction with the Notch receptors (DSL domain). Homozygous mutant mice die after birth, exhibit abnormal tooth morphology and fusions between the palatal and mandibular shelves. These results demonstrate that Notch signalling plays an essential role in tooth development.

Ameloblasts↗
PubMed1999

Ligand-receptor interactions and trans-endocytosis of Delta, Serrate and Notch: members of the Notch signalling pathway in Drosophila.

Molecular evidence has established that direct heterotypic interactions occur between the Drosophila receptor Notch and the ligands Delta and Serrate, and that homotypic interactions occur between Delta molecules on opposing cell surfaces. Using an aggregation assay developed for Drosophila cultured cells, we have compared the affinities of these interactions. We find that the heterotypic interactions between Notch and the ligands Delta and Serrate have higher affinities than homotypic interactions between Delta molecules. Contrary to previous suggestions, our evidence implies that the interactions between Serrate and Notch are similar in affinity to those between Delta and Notch. We find that Fringe does not detectably affect the ligand-receptor interactions of the Notch pathway in cultured cells. Furthermore, we find that Serrate, like Delta, is a transmembrane ligand that can participate in reciprocal trans-endocytosis of ligand and receptor between expressing cells. Our findings imply that qualitative differences between Delta- and Serrate-mediated Notch signalling depend on characteristics other than intrinsic ligand-receptor affinities or the ability to participate in reciprocal ligand and receptor trans-endocytosis.

Animals↗
PubMed2005

Activation of the Notch signaling pathway in response to pulp capping of rat molars.

Notch signaling is an evolutionarily conserved pathway that controls the developmental choices made by individual cells. Cells communicate via Notch receptors and their ligands, which direct decisions on the fate of stem cells according to the states of their neighbors. In this study we explored Notch signaling after the pulp capping of adult first upper rat molars. The wound was capped with calcium hydroxide. In situ hybridization revealed an increased expression of Notch signaling genes on day 1, which showed a tendency to decrease on day 3. Notch1 increased in the subodontoblast zone and close to the lesion limited to a few cells. Notch2 increased in pulp stroma surrounded by coronal odontoblasts. Notch1 and, especially, Notch3 expression increased, corresponding to perivascular cell groups. A low increase of ligand expression was observed near the injury with Delta1 expression along the dentin wall and Jagged1 in the stroma. Expression of the downstream target, Hes1, was observed along the lesion and adjacent dentin walls. Hes5 expression was not observed. The results indicate that Notch signaling is activated in response to injury and associated with the differentiation of pulp cells into perivascular cells and odontoblasts. The findings are consistent with the concept that the Notch pathway controls stem cell fate during pulp regeneration.

Animals↗
PubMed2006

Expression of Notch signaling pathway genes in mouse embryos lacking beta4galactosyltransferase-1.

A requirement for beta4galactosyltransferase-1 (beta4GalT-1) activity in the modulation of Notch signaling by the glycosyltransferase Fringe was previously identified in a mammalian co-culture assay. Notch signaling is necessary for the formation of somites in mammals. We therefore investigated the expression of eleven Notch pathway and somitogenic genes in E9.5 mouse embryos lacking beta4GalT-1. Four of these genes were altered in expression pattern or expression level. The Notch target genes Hes5 and Mesp2 were affected to some degree in all mutant embryos. The Notch ligand genes Dll1 and Dll3 were reduced or altered in expression in a significant proportion of mutants. While there were no differences in the number or morphology of somites in E9.5 B4galt1 null embryos, the number of lumbar vertebrae in mutant embryos differed from control littermates (P < or = 0.01). The subtlety of the in vivo phenotype may be due to redundancy since several B4galt genes related to B4galt1 are expressed during embryogenesis.

Animals↗
PubMed2004

Direct regulation of the Nrarp gene promoter by the Notch signaling pathway.

Nrarp encodes for an evolutionarily conserved small ankyrin repeat-containing protein that functions as a negative regulator of Notch signaling. Interestingly, increased Nrarp transcription was observed following induction of Notch signaling, suggesting the existence of a negative feedback loop. We show here that both mouse and human promoter regions of Nrarp share two conserved regions located approximately 2 and approximately 3 kb upstream of the transcription start site each containing a perfect putative binding site for the Notch-dependent transcription factor Su(H). A 4.4 kb genomic fragment of the mouse Nrarp locus containing those conserved regions and fused to a luciferase reporter gene showed basal promoter activity in 293T cells and this activity was strongly increased by the intracellular domain of Notch, NICD. NICD-dependent stimulation was attenuated by a dominant negative mutant of Su(H), Su(H)DBM, and was not observed in Su(H)-deficient cells (OT-11). Promoter bashing and gel shift assays revealed that the most distal putative Su(H) binding site located within the -3 kb conserved element plays a crucial role in this induction. Collectively, these results provide definitive support for direct regulation of the Nrarp gene by the Notch pathway.

Animals↗
PubMed1999

The notch signaling pathway is required to specify muscle progenitor cells in Drosophila.

Organization and function of the Notch signaling pathway in Drosophila are best understood with respect to its role in the process of selection of neural progenitor cells. However, there is evidence that, besides neurogenesis, the Notch signaling pathway is involved in several other developmental processes, one of which is the selection of muscle progenitor cells. Thus, the number of these cells is increased in neurogenic mutants, and it has been proposed that muscle progenitor cells are selected from clusters of equivalent cells expressing genes of the achaete-scute gene complex (AS-C). Here, I present evidence for the participation of additional elements of the Notch signaling pathway in myogenesis. Gal4 mediated expression of a Notch variant, E(spl) and Hairless shows that the selection of muscle progenitor cells obeys principles apparently identical to those acting at the selection of neural progenitor cells.

Animals↗
PubMed2001

Identification of chromosomal deficiencies that modify Drosophila mastermind mutant phenotypes.

Mastermind (Mam) is a component of Notch pathway signaling. In combination with the intracellular domain of Notch and Suppressor of Hairless, Mam forms a transcriptional activation complex. We have initiated a genetic approach to identify other loci involved in Mam function. The screen utilizes engineered mutations in Mam that derive from GAL4-UAS-directed expression of dominant negative constructs. When driven at the wing margin, truncated versions of Mam phenocopy Notch pathway mutations. Correlated with these phenotypes is depression of Notch pathway target expression. Strains expressing truncated versions of Mam were tested for genetic interactions with a large collection of chromosomal deficiencies. Genomic segments that enhanced and suppressed the dominant wing phenotype were identified. These regions may contain uncharacterized loci involved in Notch pathway function.

Animals↗
PubMed1996

Interaction between Wingless and Notch signaling pathways mediated by dishevelled.

In Drosophila, the Wingless and Notch signaling pathways function in m any of the same developmental patterning events. Genetic analysis demonstrates that the dishevelled gene, which encodes a molecule previously implicated in implementation of the Winglass signal, interacts antagonistically with Notch and one of its known ligands, Delta. A direct physical interaction between Dishevelled and the Notch carboxyl terminus, distal to the cdc10/ankyrin repeats, suggests a mechanism for this interaction. It is proposed that Dishevelled, in addition to transducing the Wingless signal, blocks Notch signaling directly, thus providing a molecular mechanism for the inhibitory cross talk observed between these pathways.

Adaptor Proteins, Signal Transducing↗
PubMed2001

Nrarp is a novel intracellular component of the Notch signaling pathway.

The Lin12/Notch receptors regulate cell fate during embryogenesis by activating the expression of downstream target genes. These receptors signal via their intracellular domain (ICD), which is released from the plasma membrane by proteolytic processing and associates in the nucleus with the CSL family of DNA-binding proteins to form a transcriptional activator. How the CSL/ICD complex activates transcription and how this complex is regulated during development remains poorly understood. Here we describe Nrarp as a new intracellular component of the Notch signaling pathway in Xenopus embryos. Nrarp is a member of the Delta-Notch synexpression group and encodes a small protein containing two ankyrin repeats. Nrarp expression is activated in Xenopus embryos by the CSL-dependent Notch pathway. Conversely, overexpression of Nrarp in embryos blocks Notch signaling and inhibits the activation of Notch target genes by ICD. We show that Nrarp forms a ternary complex with the ICD of XNotch1 and the CSL protein XSu(H) and that in embryos Nrarp promotes the loss of ICD. By down-regulating ICD levels, Nrarp could function as a negative feedback regulator of Notch signaling that attenuates ICD-mediated transcription.

Amino Acid Sequence↗
PubMed1997

Developmental restriction of Mash-2 expression in trophoblast correlates with potential activation of the notch-2 pathway.

Mash-2 expression begins during preimplantation development, but is restricted to trophoblasts after the blastocyst stage. Within the trophoblast lineage, Mash-2 transcripts are first expressed in the ectoplacental cone and chorion, but not in terminally differentiated trophoblast giant cells. After day 8.5 of gestation, Mash-2 expression becomes further restricted to focal sites within the spongiotrophoblast and labyrinth. Downregulation is probably important for normal development since overexpression of Mash-2 reduces giant cell formation. We have investigated the role that the Notch signaling pathway may play in trophoblast development. Mash-2 is a homologue of Drosophila achaete/scute complex genes. In Drosophila, activation of the Notch receptor induces transcriptional repressors encoded by the hairy/Enhancer of split (HES) genes, which interact with the Groucho protein to shut off achaete-scute transcription. In the developing mouse placenta, we found that all elements of the Notch pathway were expressed. In particular, the Notch-2, HES-2, and HES-3 genes were coexpressed in trophoblast giant cells and in foci within the spongiotrophoblast at day 10.5 when Mash-2 transcription becomes restricted. Two members of the mammalian Groucho family were expressed in trophoblasts; TLE3 was expressed broadly in the giant cell, spongiotrophoblast, and labyrinthine regions, whereas TLE2 was limited to giant cells and focal regions of the spongiotrophoblast. These data suggest that Notch signaling through activation of HES transcriptional repressors may play a role in murine placental development.

Animals↗