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 163 records · Page 9Linked to original sources
PubMed2006

Drosophila melanogaster auxilin regulates the internalization of Delta to control activity of the Notch signaling pathway.

We have isolated mutations in the Drosophila melanogaster homologue of auxilin, a J-domain-containing protein known to cooperate with Hsc70 in the disassembly of clathrin coats from clathrin-coated vesicles in vitro. Consistent with this biochemical role, animals with reduced auxilin function exhibit genetic interactions with Hsc70 and clathrin. Interestingly, the auxilin mutations interact specifically with Notch and disrupt several Notch-mediated processes. Genetic evidence places auxilin function in the signal-sending cells, upstream of Notch receptor activation, suggesting that the relevant cargo for this auxilin-mediated endocytosis is the Notch ligand Delta. Indeed, the localization of Delta protein is disrupted in auxilin mutant tissues. Thus, our data suggest that auxilin is an integral component of the Notch signaling pathway, participating in the ubiquitin-dependent endocytosis of Delta. Furthermore, the fact that auxilin is required for Notch signaling suggests that ligand endocytosis in the signal-sending cells needs to proceed past coat disassembly to activate Notch.

Animals↗
PubMed1998

Notch signalling pathway and human diseases.

Several homologs of the Drosophila Notch receptor and its ligands, Delta/Serrate, have been cloned in man. Three human disorders including a neoplasia (a T-cell acute lymphoblastic leukemia/lymphoma), a late onset neurological disease (CADASIL) and a developmental disorder (the Alagille syndrome) are associated with mutations in, respectively, the Notch1, Notch3 and Jagged1 genes, pointing out the broad spectrum of Notch activity in humans. We report herein on what has been learned on the role of these human Notch genes and the mechanisms leading from mutations in those genes to the observed phenotypes.

Alagille Syndrome↗
PubMed2005

The vitamin D receptor, Runx2, and the Notch signaling pathway cooperate in the transcriptional regulation of osteopontin.

Osteopontin (OPN), a glycosylated phosphoprotein that binds calcium, is present in bone extracellular matrix and has been reported to modulate both mineralization and bone resorption. Targeted disruption in mice of the vitamin D receptor (VDR) or Runx2 results in marked inhibition of OPN expression in osteoblasts. In this study, we addressed possible cross-talk between VDR and Runx2 in regulating OPN transcription. 1,25-Dihydroxyvitamin D(3) (1,25(OH)(2)D(3)) or Runx2 stimulated OPN transcription (mouse OPN promoter -777/+79) 2-3-fold. However, coexpression of Runx2 and VDR in COS-7 cells and treatment with 1,25(OH)(2)D(3) resulted in an 8-fold induction of OPN transcription, indicating for the first time functional cooperation between Runx2 and VDR in the regulation of OPN transcription. In ROS 17/2.8 and MC3T3-E1 cells that contain endogenous Runx2, AML-1/ETO, which acts as a repressor of Runx2, significantly inhibited 1,25(OH)(2)D(3) induction of OPN transcription, OPN mRNA, and protein expression. Both a Runx2 site (-136/-130) and the vitamin D response element (-757/-743) in the OPN promoter are needed for cooperative activation. Chromatin immunoprecipitation analyses showed that 1,25(OH)(2)D(3) can enhance VDR and Runx2 recruitment on the OPN promoter, further indicating cooperation between these two factors in the regulation of OPN. In osteoblastic cells, Hes-1, a downstream factor of the Notch signaling pathway, was found to enhance basal and 1,25(OH)(2)D(3)-induced OPN transcription. This enhancement was inhibited by AML-1/ETO, an inhibitor of Runx2. Immunoprecipitation assays indicated that Hes-1 and Runx2 interact and that 1,25(OH)(2)D(3) can enhance this interaction. Taken together, these findings define novel mechanisms involving the intersection of three pathways, Runx2, 1,25(OH)(2)D(3), and Notch signaling, that play a major role in the regulation of OPN in osteoblastic cells and therefore in the process of bone remodeling.

Animals↗
PubMed1994

The Notch signalling pathway is required for Enhancer of split bHLH protein expression during neurogenesis in the Drosophila embryo.

The Enhancer of split locus is required during many cell-fate decisions in Drosophila, including the segregation of neural precursors in the embryo. We have generated monoclonal antibodies that recognise some of the basic helix-loop-helix proteins encoded by the Enhancer of split locus and have used them to examine expression of Enhancer of split proteins during neurogenesis. The proteins are expressed in a dynamic pattern in the ventral neurogenic region and are confined to those ectodermal cells that surround a neuroblast in the process of delaminating. There is no staining in the neuroblasts themselves. We have also examined the relationship between Enhancer of split protein accumulation and the Notch signalling pathway. Protein expression is abolished in a number of neurogenic mutant backgrounds, including Notch, but is increased as a result of expressing a constitutively active Notch product. We conclude that Notch signalling activity is directly responsible for the accumulation of basic helix-loop-helix proteins encoded by the Enhancer of split locus.

Animals↗
PubMed2001

The p53 family member genes are involved in the Notch signal pathway.

The p53 tumor suppressor is a transcription factor that regulates cell growth and death in response to environmental stimuli such as DNA damage. p63/p51 and p73 were recently identified as members of the p53 gene family. In contrast to p53 however, p63 and p73 are rarely mutated in human cancers. Mice that lack p53 are developmentally normal, while p63 and p73 appear to play critical roles in normal development. To determine how p63 and p73 are involved in normal development, we attempted to identify target genes that are specifically regulated by p63 and/or p73 but not by p53. We found that the Jagged1 (JAG1) and Jagged2 (JAG2) genes, encoding ligands for the Notch receptors, are up-regulated by p63 and p73. Furthermore, we identified a p63-binding site in the second intron of the JAG1 gene, which can directly interact with the p63 protein in vivo, as assessed by a chromatin immunoprecipitation assay. A heterologous reporter assay revealed that this p63-binding site is a functional response element and is specific for p63. We also found a target of Notch signaling, HES-1 was up-regulated in Jurkat cells, in which Notch1 is highly expressed, when co-cultured with p63-transfected cells, suggesting that p63 can trigger the Notch signal pathway in neighboring cells. Our findings show an association between the p53 family genes and Notch signaling and suggest a potential molecular mechanism for the involvement of the p53 family genes in normal development.

Calcium-Binding Proteins↗
PubMed2005

Insertional inactivation of the L13a ribosomal protein gene of Drosophila melanogaster identifies a new Minute locus.

We have utilized a transposable P element construct to scan the genome for modifiers of Drosophila Notch pathway phenotypes. From a collection of 2000 inserts we obtained two enhancers and one suppressor. Sequence analysis of the insertion regions demonstrated that two modifiers affect known components of the Notch pathway, whereas the third is an insert in the gene encoding ribosomal protein L13a at cytogenetic region 83B6-7. The insert in the RpL13A coding region creates a classic Minute mutation which enhances Notch pathway wing phenotypes. This report adds RpL13A to the list of Drosophila ribosomal protein genes that cause Minute phenotypes when mutated.

Amino Acid Sequence↗
PubMed2005

Hematopoietic stem cell fate is established by the Notch-Runx pathway.

Identifying the molecular pathways regulating hematopoietic stem cell (HSC) specification, self-renewal, and expansion remains a fundamental goal of both basic and clinical biology. Here, we analyzed the effects of Notch signaling on HSC number during zebrafish development and adulthood, defining a critical pathway for stem cell specification. The Notch signaling mutant mind bomb displays normal embryonic hematopoiesis but fails to specify adult HSCs. Surprisingly, transient Notch activation during embryogenesis via an inducible transgenic system led to a Runx1-dependent expansion of HSCs in the aorta-gonad-mesonephros (AGM) region. In irradiated adults, Notch activity induced runx1 gene expression and increased multilineage hematopoietic precursor cells approximately threefold in the marrow. This increase was followed by the accelerated recovery of all the mature blood cell lineages. These data define the Notch-Runx pathway as critical for the developmental specification of HSC fate and the subsequent homeostasis of HSC number, thus providing a mechanism for amplifying stem cells in vivo.

Animals↗
PubMed2001

NFkappaB2 (p52) promoter activation via Notch signaling pathway in rheumatoid synoviocytes.

Rheumatoid synoviocytes produce inflammatory cytokines and exhibit strong proliferation activity, which cause severe cartilage destruction in the joints. Previously, we reported that NFkappaB, a transcriptional factor that activated by mitogenic signals, was activated in rheumatoid synoviocytes. In addition, we revealed that Notch-1, the transcriptional factor that is involved in the developmental stages, was abnormally activated in rheumatoid synoviocytes. In this study, as one of the roles of Notch-1 for the chronic inflammation in RA, we examined its implication to NFkappaB2 activation in rheumatoid synoviocytes. Western blotting analysis showed that NFkappaB2 expression was elevated in rheumatoid synoviocytes compared with patients with osteoarthritis studied as control. We then analyzed NFkappaB2 binding activity to the promoter and revealed that kappaB binding complexes to the NFkappaB2 promoter was elevated in rheumatoid synoviocytes. We analyzed implication of Notch-1 signaling pathway on NFkappaB2 activation, and found that Notch-1 made a complex with recombination binding protein Jkappa (RBPJkappa), a repressor for NFkappaB2 promoter, and blocked binding of RBPJkappa to the promoter. These results indicated that as one of the mechanisms for nuclear translocated Notch-1, complex formation with RBPJkappa induces blocking of the NFkappaB2 promoter suppression, which might cause NFkappaB2 promoter activation.

Arthritis, Rheumatoid↗
PubMed2004

Notch inhibits Ptf1 function and acinar cell differentiation in developing mouse and zebrafish pancreas.

Notch signaling regulates cell fate decisions in a variety of adult and embryonic tissues, and represents a characteristic feature of exocrine pancreatic cancer. In developing mouse pancreas, targeted inactivation of Notch pathway components has defined a role for Notch in regulating early endocrine differentiation, but has been less informative with respect to a possible role for Notch in regulating subsequent exocrine differentiation events. Here, we show that activated Notch and Notch target genes actively repress completion of an acinar cell differentiation program in developing mouse and zebrafish pancreas. In developing mouse pancreas, the Notch target gene Hes1 is co-expressed with Ptf1-P48 in exocrine precursor cells, but not in differentiated amylase-positive acinar cells. Using lentiviral delivery systems to induce ectopic Notch pathway activation in explant cultures of E10.5 mouse dorsal pancreatic buds, we found that both Hes1 and Notch1-IC repress acinar cell differentiation, but not Ptf1-P48 expression, in a cell-autonomous manner. Ectopic Notch activation also delays acinar cell differentiation in developing zebrafish pancreas. Further evidence of a role for endogenous Notch in regulating exocrine pancreatic differentiation was provided by examination of zebrafish embryos with homozygous mindbomb mutations, in which Notch signaling is disrupted. mindbomb-deficient embryos display accelerated differentiation of exocrine pancreas relative to wild-type clutchmate controls. A similar phenotype was induced by expression of a dominant-negative Suppressor of Hairless [Su(H)] construct, confirming that Notch actively represses acinar cell differentiation during zebrafish pancreatic development. Using transient transfection assays involving a Ptf1-responsive reporter gene, we further demonstrate that Notch and Notch/Su(H) target genes directly inhibit Ptf1 activity, independent of changes in expression of Ptf1 component proteins. These results define a normal inhibitory role for Notch in the regulation of exocrine pancreatic differentiation.

Adenoviridae↗
PubMed2001

The loss of Drosophila APG4/AUT2 function modifies the phenotypes of cut and Notch signaling pathway mutants.

A P-element line ( P0997) of Drosophila melanogaster in which the P element disrupts the Drosophila homolog of the Saccharomyces cerevisiae gene APG4/AUT2 was identified during the course of screening for cut ( ct) modifiers. The yeast gene APG4/AUT2 encodes a cysteine endoprotease directed against Apg8/Aut7 and is necessary for autophagy. The P0997 mutation enhances the wing margin loss associated with ct mutations, and also modifies the wing and eye phenotypes of Notch (N), Serrate (Ser), Delta (Dl), Hairless (H), deltex (dx), vestigial (vg) and strawberry notch (sno) mutants. These results therefore suggest an unexpected link between autophagy and the Notch signaling pathway.

Amino Acid Sequence↗
PubMed2002

Establishment of dental epithelial cell line (HAT-7) and the cell differentiation dependent on Notch signaling pathway.

Rat incisors grow continuously throughout life. Producing a variety of dental epithelial cells is performed by stem cells located in the cervical loop of the incisor apex. To study the mechanisms for cell differentiation, we established a dental epithelial cell line (HAT-7) originating from a cervical loop epithelium of a rat incisor. Immunochemical studies showed that HAT-7 produced the cells expressing amelogenin, ameloblastin, or alkaline phosphatase (ALP). To illustrate a role of Notch signaling in the determinant of the cell fate, we examined expression patterns of Notch1 and Jagged1 in HAT-7 density dependently. At lower cell density, Notch1- or Jagged1-expressing cells were not seen. However, when they were fully confluent, cells began to express Notch1 or Jagged1 strongly. Some ALP-positive cells were almost consistent with Notch1-expressing cells but not Jagged1-expressing cells. These results suggested that the determinant of direction of differentiation was associated with Notch signaling pathway.

Animals↗
PubMed2003

Echinoid synergizes with the Notch signaling pathway in Drosophila mesothorax bristle patterning.

echinoid (ed) encodes an immunoglobulin domain-containing cell adhesion molecule that negatively regulates the Egfr signaling pathway during Drosophila photoreceptor development. We show a novel function of Ed, i.e. the restriction of the number of notum bristles that arise from a proneural cluster. Thus, loss-of-function conditions for ed give rise to the development of extra macrochaetae near the extant ones and increase the density of microchaetae. Analysis of ed mosaics indicates that extra sensory organ precursors (SOPs) arise from proneural clusters of achaete-scute expression in a cell-autonomous way. ed embryos also exhibit a neurogenic phenotype. These phenotypes suggest a functional relation between ed and the Notch (N) pathway. Indeed, loss-of-function of ed reduces the expression of the N pathway effector E(spl)m8 in proneural clusters. Moreover, combinations of moderate loss-of-function conditions for ed and for different components of the N pathway show clear synergistic interactions manifested as strong neurogenic bristle phenotypes. We conclude that Ed is not essential for, but it facilitates, N signaling. It is known that the N and Egfr pathways act antagonistically in bristle development. Consistently, we find that Ed also antagonizes the bristle-promoting activity of the Egfr pathway, either by the enhancement of N signalling or, similar to the eye, by a more direct action on the Egfr pathway.

Amino Acid Sequence↗
PubMed1999

Notch signalling pathway mediates hair cell development in mammalian cochlea.

The mammalian cochlea contains an invariant mosaic of sensory hair cells and non-sensory supporting cells reminiscent of invertebrate structures such as the compound eye in Drosophila melanogaster. The sensory epithelium in the mammalian cochlea (the organ of Corti) contains four rows of mechanosensory hair cells: a single row of inner hair cells and three rows of outer hair cells. Each hair cell is separated from the next by an interceding supporting cell, forming an invariant and alternating mosaic that extends the length of the cochlear duct. Previous results suggest that determination of cell fates in the cochlear mosaic occurs via inhibitory interactions between adjacent progenitor cells (lateral inhibition). Cells populating the cochlear epithelium appear to constitute a developmental equivalence group in which developing hair cells suppress differentiation in their immediate neighbours through lateral inhibition. These interactions may be mediated through the Notch signalling pathway, a molecular mechanism that is involved in the determination of a variety of cell fates. Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium. In addition, genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as a result of a decrease in Notch activation. These results provide direct evidence for Notch-mediated lateral inhibition in a mammalian system and support a role for Notch in the development of the cochlear mosaic.

Animals↗
PubMed2004

LEF1-mediated regulation of Delta-like1 links Wnt and Notch signaling in somitogenesis.

Wnt signaling, which is mediated by LEF1/TCF transcription factors, has been placed upstream of the Notch pathway in vertebrate somitogenesis. Here, we examine the molecular basis for this presumed hierarchy and show that a targeted mutation of Lef1, which abrogates LEF1 function and impairs the activity of coexpressed TCF factors, affects the patterning of somites and the expression of components of the Notch pathway. LEF1 was found to bind multiple sites in the Dll1 promoter in vitro and in vivo. Moreover, mutations of LEF1-binding sites in the Dll1 promoter impair expression of a Dll1-LacZ transgene in the presomitic mesoderm. Finally, the induced expression of LEF1-beta-catenin activates the expression of endogenous Dll1 in fibroblastic cells. Thus, Wnt signaling can affect the Notch pathway by a LEF1-mediated regulation of Dll1.

Animals↗
PubMed2006

Cerebellar arteriovenous malformation and vertebral artery aneurysm in a CADASIL patient.

The presence of large vessels malformations has not been reported in cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). We describe a CADASIL patient in whom a brain cerebellar arteriovenous malformation was revealed by magnetic resonance (MR) imaging. An MR angiogram documented also an aneurysm along the right intracranial vertebral artery at the junction with the posterior-inferior cerebellar artery. The aneurysm was successfully treated by means of endovascular coil embolization. No neurological complication occurred in our patient during the angiographic procedure. In this case, in addition to an incidental coexistence of CADASIL and large vessels abnormalities, a causal role of the Notch pathway alteration could be hypothesized. Dysregulation of the Notch pathway is linked to several human diseases besides CADASIL. In one of these (the Alagille syndrome) intracranial aneurysms are reported. This hypothesis contrasts however with the absence of similar reports in other CADASIL cases and needs corroboration in large series.

Adult↗
PubMed2001

HERP1 is a cell type-specific primary target of Notch.

Notch signaling is involved in many cell fate determination events in metazoans. Ligand binding results in proteolytic cleavage to release the signal-transducing Notch intracellular domain (NICD). The nuclear protein RBP-J kappa, when complexed with NICD, acts as a transcriptional activator which, in turn, induces a target gene of Notch such as the repressors HES/E(spl) and HERP2. Under physiological stimulation using co-culture with Notch ligand-expressing cells and target cells expressing Notch receptors, the HES1 gene and the HERP2 gene have been shown to be directly up-regulated by Notch ligand binding. However, expression of another member of the HERP family, HERP1, was not induced by ligand stimulation in any cells tested, leading to the suggestion that HERP1 may not be an immediate target of Notch or that Notch pathways can be cell type-specific. Because HERP1 appears to play a central role in the development of the aorta (Zhong, T. P., Rosenberg, M., Mohideen, M. A., Weinstein, B., and Fishman, M. C. (2000) Science 287, 1820-1824), we re-addressed the issue of its relationship with the Notch pathway by examining its expression in A10 smooth muscle cells derived from thoracic aorta. We show that in these specific cells HERP1 is also a direct target gene of Notch. NICD activates the HERP1 promoter in an RBP-J kappa-dependent manner, and induces expression of endogenous HERP1 mRNA as well as HERP1 protein in A10 cells. Co-culture with Notch ligand-bearing cells induces endogenous HERP1 mRNA expression in A10 cells, and these events occur even in the absence of de novo protein synthesis. In addition, RBP-J kappa proved essential for induction of HERP1 mRNA in Notch signaling because exogenous RBP-J kappa was sufficient to rescue HERP1 mRNA expression in RBP-J kappa-deficient cells. These findings provide the first solid evidence that HERP1 is a novel primary target of Notch and underscores the cell-specific complexity of the Notch regulatory pathway. Given that Notch signaling plays a crucial role in vascular development, Notch may derive its function via HERP family members.

Amino Acid Sequence↗
PubMed2004

Notch activation induces endothelial cell cycle arrest and participates in contact inhibition: role of p21Cip1 repression.

Although previous studies demonstrate that appropriate Notch signaling is required during angiogenesis and in vascular homeostasis, the mechanisms by which Notch regulates vascular function remain to be elucidated. Here, we show that activation of the Notch pathway by the ligand Jagged1 reduces the proliferation of endothelial cells. Notch activation inhibits proliferation of endothelial cells in a cell-autonomous manner by inhibiting phosphorylation of the retinoblastoma protein (Rb). During cell cycle entry, p21Cip1 is upregulated in endothelial cells. Activated Notch inhibits mitogen-induced upregulation of p21Cip1 and delays cyclin D-cdk4-mediated Rb phosphorylation. Notch-dependent repression of p21Cip1 prevents nuclear localization of cyclin D and cdk4. The necessity of p21Cip1 for nuclear translocation of cyclin D-cdk4 and S-phase entry in endothelial cells was demonstrated by targeted downregulation of p21Cip1 by using RNA interference. We further demonstrate that when endothelial cells reach confluence, Notch is activated and p21Cip1 is downregulated. Inhibition of the Notch pathway at confluence prevents p21Cip1 downregulation and induces Rb phosphorylation. We suggest that Notch activation contributes to contact inhibition of endothelial cells, in part through repression of p21Cip1 expression.

Active Transport, Cell Nucleus↗
PubMed2005

Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis.

Spontaneous and engineered mutations in the Notch ligand Jagged2 produced the Syndactylism phenotype (Jiang, R.L., Lan, Y., Chapman, H.D., Shawber, C., Norton, C.R., Serreze, D.V., Weinmaster, G., Gridley, T., 1998. Defects in limb, craniofacial, and thymic Development in Jagged2 mutant mice. Genes Dev. 12, 1046-1057; Sidow, A., Bulotsky, M.S., Kerrebrock, A.W., Bronson, R.T., Daly, M.J., Reeve, M.P., Hawkins, T.L., Birren, B.W., Jaenisch, R., Lander, E.S., 1997. Serrate2 is disrupted in the mouse limb-development mutant syndactylism. Nature 389, 722-725). Given that additional ligands may be expressed in the developing limb bud, it was possible that loss of Jagged2 disabled only part of Notch function in the limb. In addition, it is not clear from the expression pattern of Jagged2 in the apical ectodermal ridge (AER) whether the ectodermal or mesenchymal compartment of the limb bud receives the Jagged2 signal. To elucidate the requirement for the Notch pathway in limb development, we have analyzed single and compound Notch receptor mutants as well as gamma-secretase-deficient limbs. Floxed alleles were removed either from the developing limb bud ectoderm (using Msx2-Cre) or from the mesenchyme (using Prx1-Cre). Our results confirm that Jagged2 loss describes the contribution of the entire Notch pathway to the mouse limb development and revealed that both Notch1 and 2 are required in the ectoderm to receive the Jagged2 signal. Interestingly, our allelic series allowed us to determine that Notch receives this signal at an early stage in the developmental process and that memory of this event is retained by the mesenchyme, where Notch signaling appears to be dispensable. Thus, Notch signaling plays a non-autonomous role in digit septation.

Animals↗