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Results for “Notch pathway”

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PubMed2005

beamter/deltaC and the role of Notch ligands in the zebrafish somite segmentation, hindbrain neurogenesis and hypochord differentiation.

The Tübingen large-scale zebrafish genetic screen completed in 1996 identified a set of five genes required for orderly somite segmentation. Four of them have been molecularly identified and three were found to code for components of the Notch pathway, which are required for the coordinated oscillation of gene expression, known as the segmentation clock, in the presomitic mesoderm (PSM). Here, we show that the final member of the group, beamter (bea), codes for the Notch ligand DeltaC, and we present and characterize two new alleles, including one allele encoding for a protein truncated in the 7th EGF repeat and an allele deleting only the DSL domain which was previously shown to be necessary for ligand function. Interestingly however, when we over-express any of the mutant deltaC mRNAs, we observe antimorphic effects on both hindbrain neurogenesis and hypochord formation. Expression of bea/deltaC oscillates in the PSM, and a triple fluorescent in situ analysis of its oscillation in relation to that of other oscillating genes in the PSM reveals differences in subcellular localization of the oscillating mRNAs in individual cells in different oscillation phases. Mutations in aei/deltaD and bea/deltaC differ in the way they disrupt the oscillating expression of her1 and deltaC. Furthermore, we find that the double mutants have significantly stronger defects in hypochord formation but not in somitogenesis or hindbrain neurogenesis, indicating genetically that the two delta's may function either semi-redundantly or distinctly, depending upon context.

Alleles↗
PubMed1998

Monogenic determinants of familial Alzheimer's disease: presenilin-2 mutations.

Presenilin-2 (PS2) is one of three genes [amyloid precursor protein (APP), presenilin-1 (PS1) and PS2] shown to cause familial Alzheimer's disease (FAD), and is highly homologous to PS1. Currently demonstrated functions of PS2 include interactions with APP and A beta, and participation in apoptotic pathways. PS2 FAD mutations influence APP processing in a manner predicted to promote amyloid formation and also enhance the proapoptotic effect of wild-type PS2. Other possible functions of PS2 are related to its homology to Notch pathway genes in Caenorhabditis elegans, suggesting it may have a developmental role. PS2-associated AD is the most reminiscent of the sporadic form of the disease in terms of older age of onset and longer disease duration. Since PS2 mutations are incompletely penetrant and age of onset in carriers is highly variable (40-88 years), elucidation of PS2 mechanisms may reveal factors which modify AD and are therapeutically relevant to sporadic AD.

Adult↗
PubMed2003

Mind bomb is a ubiquitin ligase that is essential for efficient activation of Notch signaling by Delta.

Lateral inhibition, mediated by Notch signaling, leads to the selection of cells that are permitted to become neurons within domains defined by proneural gene expression. Reduced lateral inhibition in zebrafish mib mutant embryos permits too many neural progenitors to differentiate as neurons. Positional cloning of mib revealed that it is a gene in the Notch pathway that encodes a RING ubiquitin ligase. Mib interacts with the intracellular domain of Delta to promote its ubiquitylation and internalization. Cell transplantation studies suggest that mib function is essential in the signaling cell for efficient activation of Notch in neighboring cells. These observations support a model for Notch activation where the Delta-Notch interaction is followed by endocytosis of Delta and transendocytosis of the Notch extracellular domain by the signaling cell. This facilitates intramembranous cleavage of the remaining Notch receptor, release of the Notch intracellular fragment, and activation of target genes in neighboring cells.

Animals↗
PubMed2004

The vertebrate segmentation clock.

In vertebrate embryos, somite segmentation is controlled by a molecular clock, in the form of a transcriptional oscillator that operates in the presomitic mesoderm. Most of the genes implicated in the oscillator belong to the Notch pathway; a recently discovered exception is the Wnt pathway gene Axin2. Experiments have revealed several negative feedback loops that might generate oscillations, leading to at least four different theories. The simplest of these is based on direct autoinhibition of certain members of the hairy/E(spl) family of Notch target genes--Hes7 in the mouse, and her1 and her7 in the zebrafish. A mathematical account of this mechanism explains some surprising observations and suggests that the period of oscillation is chiefly determined by the transcriptional and translational delays--the times required to make a molecule of the mRNA and a molecule of the protein.

Animals↗
PubMed2002

Notch signalling is linked to epidermal cell differentiation level in basal cell carcinoma, psoriasis and wound healing.

BACKGROUND: Epidermal homeostasis involves the monitoring of continuous proliferative and differentiative processes as keratinocytes migrate from the basal layer to the skin surface. Recently, differentiation of epidermal stem cells was shown to be promoted by the Notch pathway. This pathway is characterised by cell-cell interactions between transmembrane proteins and was first implicated in lateral inhibition, patterning and cell binary choices during embryogenesis. METHODS: By in situ hybridisation, we investigated the in vivo expression of related genes, namely; Notch 1-3, Delta 1, Jagged 1, Lunatic Fringe, Radical Fringe and Manic Fringe during keratinocyte proliferation and differentiation in humans in basal cell carcinoma, psoriasis and in wound healing experiments, compared with normal adult skin. RESULTS: We show that the highest level of transcription of these genes is in the basal cell layer of non-lesional skin. Conversely, when keratinocytes were hyperproliferating, as in basal cell carcinoma, psoriasis, and during the first step of re-epithelialisation, expression was weak or non-existent. Furthermore, normal levels of transcripts were rescued in psoriatic plaques when treated by phototherapy, as well as in newly regenerated stratified epidermis following wound healing. CONCLUSION: The Notch signalling involved in the differentiation programme of normal adult human epidermis is altered under experimental conditions and pathologies which modify this programme.

Adult↗
PubMed2006

Canonical Wnt signaling transiently stimulates proliferation and enhances neurogenesis in neonatal neural progenitor cultures.

Canonical Wnt signaling triggers the formation of heterodimeric transcription factor complexes consisting of beta-catenin and T cell factors, and thereby controls the execution of specific genetic programs. During the expansion and neurogenic phases of embryonic neural development canonical Wnt signaling initially controls proliferation of neural progenitor cells, and later neuronal differentiation. Whether Wnt growth factors affect neural progenitor cells postnatally is not known. Therefore, we have analyzed the impact of Wnt signaling on neural progenitors isolated from cerebral cortices of newborn mice. Expression profiling of pathway components revealed that these cells are fully equipped to respond to Wnt signals. However, Wnt pathway activation affected only a subset of neonatal progenitors and elicited a limited increase in proliferation and neuronal differentiation in distinct subsets of cells. Moreover, Wnt pathway activation only transiently stimulated S-phase entry but did not support long-term proliferation of progenitor cultures. The dampened nature of the Wnt response correlates with the predominant expression of inhibitory pathway components and the rapid actuation of negative feedback mechanisms. Interestingly, in differentiating cell cultures activation of canonical Wnt signaling reduced Hes1 and Hes5 expression suggesting that during postnatal neural development, Wnt/beta-catenin signaling enhances neurogenesis from progenitor cells by interfering with Notch pathway activity.

Animals↗
PubMed2006

The Drosophila Notch inhibitor and tumor suppressor gene lethal (2) giant discs encodes a conserved regulator of endosomal trafficking.

Notch signaling is involved in many developmental and pathological processes, and its activity must be precisely controlled in order to prevent aberrant development and disease. We have previously shown that the tumor suppressor gene lethal (2) giant discs (lgd) is required to prevent ectopic activation of Notch in developmental processes in Drosophila. Here we show that lgd is required in all imaginal disc cells to suppress the activity of the Notch pathway. lgd encodes a member of a poorly characterized protein family present in all animals, which includes a member that is involved in an inheritable form of mental retardation in humans. Our analysis reveals that Lgd is required for endosomal trafficking of Notch and other proteins. In the absence of Lgd, Notch is activated in a ligand-independent manner in probably all imaginal disc cells in an endosomal compartment downstream of the block in hrs mutants.

Animals↗
PubMed2000

Imbalanced expression of TAN-1 and human Notch4 in endometrial cancers.

The development of cancer is a cellular process that reflects and is partly driven by alterations in cell determination. Mutations in various genes responsible for cell determination have been identified as being oncogenic; however, little is known about the involvement of normal cell fate-determining mechanisms in the oncogenic process. The Notch pathway is an evolutionarily conserved, general cell-interaction mechanism that controls fundamental aspects of cell determination during the development of vertebrates and invertebrates. We have explored the roles of the recently cloned human Notch4 gene, which is a homologue of Drosophila Notch, in endometrial tissue, a cellular environment where cell fate changes take place and neoplastic conditions have been characterized. Northern blot analysis, dot blot analysis, and in situ hybridization were performed on samples of normal endometria at different phases of the menstrual cycle and endometrial cancers. Our results showed that: a) Both human Notch4 and translocation-associated Notch homologue-1 (TAN-1), another human homologue of Drosophila Notch, are expressed in the normal endometrium, mainly in the endometrial glandular cells. b) The level of expression of human Notch4, but not TAN-1, changes during the normal menstrual cycle; i.e., the level of Notch4 expression was significantly lower during the secretory phase than during the proliferative phase. c) Endometrial cancers express a significantly lower level of human Notch4 and a significantly higher level of TAN-1 than normal endometria. These results suggest that human Notch4 and/or TAN-1 are involved in the changes of the endometrium during the menstrual cycle, and also in the development of endometrial cancer.

Adenocarcinoma↗
PubMed2003

[The generation of neural stem cells: induction of neural stem cells from embryonic stem (ES) cells].

Neural stem cells are considered the ultimate lineage precursors to all neurons and glia. Despite the significance of neural stem cells in the mammalian brain development, their ontogenesis remains unclear. We have established a colony-forming embryonic stem (ES) sphere assay, where ES cells were cultured in serum-free media in the presence of leukemia inhibitory factor (LIF) to form floating spheres. LIF-dependent ES cell-derived sphere cells showed self-renewal and neural multipotentiality, cardinal features of the neural stem cell, but retained some non-neural properties and broader potential. We dabbed the cells in the ES cell-derived sphere of primitive neural stem cells. LIF-dependent sphere-forming cells were also present in the epiblast of embryonic day 5.5-7.5 mouse embryos. The generation of the in vivo primitive neural stem cell was independent of Notch signaling but the activation of Notch pathway was necessary for the transition from the primitive neural stem cell to the neural stem cell. We propose that the neural stem cell originates from the pluripotent inner cell mass/epiblast cell via the primitive neural stem cell stage under the control of Notch signaling.

Animals↗
PubMed2005

Progenitors resume generating neurons after temporary inhibition of neurogenesis by Notch activation in the mammalian cerebral cortex.

The mammalian cerebral cortex comprises six layers of neurons. Cortical progenitors in the ventricular zone generate neurons specific to each layer through successive cell divisions. Neurons of layer VI are generated at an early stage, whereas later-born neurons occupy progressively upper layers. The underlying molecular mechanisms of neurogenesis, however, are relatively unknown. In this study, we devised a system where the Notch pathway was activated spatiotemporally in the cortex by in vivo electroporation and Cre-mediated DNA recombination. Electroporation at E13.5 transferred DNA to early progenitors that gave rise to neurons of both low and upper layers. Forced expression of a constitutively active form of Notch (caNotch) at E13.5 inhibited progenitors from generating neurons and kept progenitors as proliferating radial glial cells. After subsequent transfection at E15.5 of a Cre expression vector to remove caNotch, double-transfected cells, in which caNotch was excised, migrated into the cortical plate and differentiated into neurons specific to upper layers. Bromodeoxyuridine-labeling experiments showed that the neurons were born after Cre transfection. These results indicate that cortical progenitors that had been temporarily subjected to Notch activation at an early stage generated neurons at later stages, but that the generation of low-layer neurons was skipped. Moreover, the double-transfected cells gave rise to upper-layer neurons, even after their transplantation into the E13.5 brain, indicating that the developmental state of progenitors is not halted by caNotch activity.

Animals↗
PubMedDate not supplied

Notch signaling in cancer.

Notch signaling plays a key role in the normal development of many tissues and cell types, through diverse effects on differentiation, survival, and/or proliferation that are highly dependent on signal strength and cellular context. Because perturbations in the regulation of differentiation, survival, and/or proliferation underlie malignant transformation, pathophysiologic Notch signals potentially contribute to cancer development in several different ways. Notch signaling was first linked to tumorigenesis through identification of a recurrent t(7;9)(q34;q34.3) chromosomal translocation involving the human Notch1 gene that is found in a small subset of human pre-T-cell acute lymphoblastic leukemias (T-ALL).(1) Since this discovery, aberrant Notch signaling has been suggested to be involved in a wide variety of human neoplasms. In this review, we will focus on recent studies linking aberrant Notch signaling with cancer. First, we discuss various mechanisms through which Notch signaling may influence cellular transformation. Then, we critically review literature pertaining to the role of Notch signaling in several cancers, and discuss possible therapeutic targets in the Notch pathway.

Animals↗
PubMed2005

Negative feedback regulation of Met-dependent invasive growth by Notch.

The hepatocyte growth factor (HGF) receptor encoded by the Met oncogene controls a genetic program-known as "invasive growth"-responsible for several developmental processes and involved in cancer invasion and metastasis. This program functions through several regulatory gene products, as yet largely unknown, both upstream and downstream of Met. Here we show that activation of the Notch receptor results in transcriptional down-regulation of Met, suppression of HGF-dependent Ras signaling, and impairment of HGF-dependent cellular responses. In turn, Met activation leads to transcriptional induction of the Notch ligand Delta and the Notch effector HES-1, indicating that Met is able to self-tune its own protein levels and the ensuing biochemical and biological outputs through stimulation of the Notch pathway. By using branching morphogenesis of the tracheal system in Drosophila as a readout of invasive growth, we also show that exogenous expression of a constitutively active form of human Met induces enhanced sprouting of the tracheal tree, a phenotype that is further increased in embryos lacking Notch function. These results unravel an in-built mechanism of negative feedback regulation in which Met activation leads to transcriptional induction of Notch function, which in turn limits HGF activity through repression of the Met oncogene.

Animals↗
PubMed2004

Papillomavirus-mediated neoplastic progression is associated with reciprocal changes in JAGGED1 and manic fringe expression linked to notch activation.

Infection by high-risk human papillomaviruses (HPV) and persistent expression of viral oncogenes E6 and E7 are causally linked to the development of cervical cancer. These oncogenes are necessary but insufficient for complete transformation of human epithelial cells in vivo. Intracellular Notch1 protein is detected in invasive cervical carcinomas (ICC), and truncated Notch1 alleles complement the function of E6/E7 in the transformation of human epithelial cells. Here we investigate potential mechanisms of Notch activation in a human cervical neoplasia. We have analyzed human cervical lesions and serial passages of an HPV type 16-positive human cervical low-grade lesion-derived cell line, W12, that shows abnormalities resembling those seen in cervical neoplastic progression in vivo. Late-passage, but not early-passage, W12 and progression of the majority of human high-grade cervical lesions to ICC showed upregulation of Notch ligand and Jagged1 and downregulation of Manic Fringe, a negative regulator of Jagged1-Notch1 signaling. Concomitantly, an increase in Notch/CSL (CBF1, Suppressor of Hairless, Lag1)-driven reporter activity and a decrease in Manic Fringe upstream regulatory region (MFng-URR)-driven reporter activity was observed in late-passage versus early passage W12. Analysis of the MFng-URR revealed that Notch signaling represses this gene through Hairy Enhancer of Split 1, a transcriptional target of the Notch pathway. Expression of Manic Fringe by a recombinant adenovirus, dominant-negative Jagged1, or small interfering RNA against Jagged1 inhibits the tumorigenicity of CaSki, an ICC-derived cell line that was previously shown to be susceptible to growth inhibition induced by antisense Notch1. We suggest that activation of Notch in cervical neoplasia is Jagged1 dependent and that its susceptibility to the influence of Manic Fringe is of therapeutic value.

3T3 Cells↗
PubMed2004

Notch signaling controls hepatoblast differentiation by altering the expression of liver-enriched transcription factors.

Hepatoblasts give rise to both mature hepatocytes and cholangiocytes. While Notch signaling has been implicated in the formation of bile ducts composed of cholangiocytes, little is known about the mechanism of lineage commitment of hepatoblasts. Here we describe the role of the Notch pathway in hepatoblast differentiation. Immunohistochemical analysis showed that Jagged1 was expressed in the cells surrounding the portal veins and Notch2 was expressed in most hepatic cells at mid gestation when ductal plates are formed surrounding the portal veins. Interestingly, the Jagged1+ cells were adjacent to ductal plates, suggesting that the Notch signaling is activated in hepatoblasts that undergo differentiation into cholangiocytes. In fact, expression of the Notch intracellular domain in Dlk+ hepatoblasts inhibited hepatic differentiation and significantly reduced the expression of albumin, a marker of both hepatoblasts and hepatocytes. Furthermore, the addition of Matrigel to the hepatoblast culture upregulated the expression of cytokeratin 7 and 19, integrin beta4, and HNF1beta, which are known to be expressed in cholangiocytes. By contrast, downregulation of the Notch signaling by siRNA specific for Notch2 mRNA as well as by the gamma-secretase inhibitor L-685,458 promoted the hepatic differentiation. Consistent with the previous finding that mature cholangiocytes strongly express HNF1beta, but barely express HNF1alpha, HNF4, and C/EBPalpha, activation of the Notch signaling upregulated HNF1beta expression, whereas it downregulated the expression of HNF1alpha, HNF4, and C/EBPalpha. These results suggest that the Notch signaling contributes to form a network of these transcription factors suitable for cholangiocyte differentiation.

Animals↗
PubMed2005

Changes in the expression of Hes5 and Mash1 mRNA in the adult rat dentate gyrus after transient forebrain ischemia.

Accumulating evidence indicates that neurogenesis in the adult brain occurs in restricted brain regions, including the hippocampal dentate gyrus and is promoted by ischemia. The mechanism responsible for ischemia-induced neurogenesis in the adult brain, however, remains unclear. Notch pathway plays a pivotal role in the regulation of the timing for differentiation and determination of the fate of neural progenitor cells in the developing nervous system. To elucidate the mechanism underlying ischemia-induced neurogenesis, we investigated changes in the expression of mRNAs of Hes5, which is a downstream target of Notch, and Mash1, a neurogenic basic helix-loop-helix factor, which is negatively regulated by Hes5, in the adult hippocampal dentate gyrus after transient forebrain ischemia. Transient forebrain ischemia was produced by four-vessel occlusion procedure in rats. The levels of Hes5 mRNA decreased on days 1 and 3 after the start of reperfusion and the decreased levels of the mRNA returned to the basal level by 5 days after ischemia. In contrast, the level of Mash1 mRNA increased on day 1 and then returned to the basal level by 3 days after ischemia. These results suggest that an inhibition of Notch activity and subsequent expression of neurogenic basic helix-loop-helix factors, including Mash1, may, at least in part, contribute to ischemia-induced neurogenesis in the adult dentate gyrus.

Animals↗
PubMed1997

Secreted forms of DELTA and SERRATE define antagonists of Notch signaling in Drosophila.

We examined the function of secreted forms of the two known Drosophila Notch ligands, DELTA and SERRATE, by expressing them under various promoters in the Drosophila developing eye and wing. The phenotypes associated with the expression of secreted Delta (DlS) or secreted Serrate (SerS) forms mimic loss-of-function mutations in the Notch pathway. Both genetic interactions between DlS or SerS transgenics and duplications or loss-of-function mutations of Delta or Serrate indicate that DlS and SerS behave as dominant negative mutations. These observations were extended to the molecular level by demonstrating that the expression of Enhancer of split mdelta, a target of Notch signaling, is down-regulated by SERS. The antagonistic nature of the two mutant secreted ligand forms in the eye is consistent with their behavior in the wing, where they are capable of down-regulating wing margin specific genes opposite to the effects of the endogenous ligands. This analysis uncovers secreted molecular antagonists of Notch signaling and provides evidence of qualitative differences in the actions of the two ligands DLS and SERS.

Animals↗
PubMed2006

Notch receptor encodes two structurally separable functions in Drosophila: a genetic analysis.

The Notch gene of Drosophila encodes a single transmembrane receptor that plays a central role in the process of lateral inhibition. This process results in the selection of individual mesodermal and neural precursors during the development of the muscular and nervous systems. The activation of Notch during lateral inhibition is mediated by the transmembrane ligand Delta (Dl) and effected by the transcription factor Suppressor of Hairless (Su(H)). The same functional cassette plays a role in other processes, in particular, the development and patterning of the wing. Genetic analysis has suggested that, in addition to the Su(H)-dependent pathway, Notch can signal in an Su(H)-independent manner. This process seems to be tightly associated with signalling by Wingless, a member of the Wnt family of signalling molecules. Here, we have analyzed further the possibility that the Notch protein encodes two different functions. To do so, we have studied the activities and genetic properties of different Notch receptors bearing deletions of specific regions of the intracellular and the extracellular domains in different developmental processes, and have sought to correlate the activity of these mutant proteins with those of existing mutants in Notch. Our results support the existence of at least two different activities of Notch each of which can be associated with specific structural domains.

Animals↗
PubMed2003

Overexpression of the Notch ligand, Jagged-1, induces alloantigen-specific human regulatory T cells.

Graft-versus-host disease (GVHD) represents one of the major complications of allogeneic hematopoietic stem cell transplantation. Techniques to prevent GVHD have included ex vivo T-cell depletion of the graft or prolonged in vivo immunosuppression. Both reduce the frequency and severity of GVHD but also reduce T-cell-mediated graft-versus-malignancy effect, and increase the risk of infection. A major goal in transplantation is to prevent alloreactivity while preserving activity against tumors and infectious agents. We have used activation of the Notch pathway to try to generate T cells able to specifically regulate alloantigen responses. We used allogeneic Epstein-Barr virus lymphoblastoid B cells (EBV-LCLs) as stimulator cells. Such LCLs are excellent (allo) antigen-presenting cells and can be obtained in large numbers even from donors who have received extensive chemo/radiotherapy. We overexpressed a Notch ligand, Jagged-1, in these cells by adenoviral vector transduction. Stimulation of CD45RA+ naive T cells by Jagged-1 EBV-LCL reduces production of interferon-gamma, interleukin-2, and interleukin-5, but up-regulates transforming growth factor-beta 1 synthesis, consistent with induction of a regulatory T-cell phenotype. Transfer of these T cells to fresh lymphocyte cultures inhibits proliferative and cytotoxic immune responses to the priming alloantigens while sparing responses to third-party stimulator cells. Notch activation in the presence of alloantigen-presenting cells may therefore be a means of inducing specific regulatory T cells while preserving other T-cell functionality.

B-Lymphocytes↗