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Results for “Notch pathway”

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At least 667 records · Page 37Linked to original sources
PubMed2003

HRT1 modulates vascular smooth muscle cell proliferation and apoptosis.

The Notch signaling pathway plays vital roles in vascular development and homeostasis. However, the functional role of HRT1, a primary downstream effector of Notch signaling in VSMC, is poorly characterized. In the present study, we postulated that HRT1 plays fundamental roles in modulating VSMC fate. To test the hypothesis that HRT1 is coupled to growth regulation, we generated VSMC lines constitutively overexpressing HRT1 (HRT1SMC) and demonstrated an exaggerated growth behavior compared to its control cell line. The lack of cell cycle arrest at confluence in HRT1SMC was associated with an attenuated up-regulation of the cell cycle inhibitor, p21(WAF1/CIP1). We further established that both transient and constitutive HRT1 signaling promoted VSMC survival in response to serum deprivation and pro-apoptotic Fas ligand. Resistance to apoptosis was associated with the induction of Akt expression/activity, a well-described anti-apoptotic mediator. Overall, these findings provide initial evidence that HRT1 functions as a critical determinant of VSMC proliferation and survival.

Animals↗
PubMed2004

Jun blockade of erythropoiesis: role for repression of GATA-1 by HERP2.

Although Jun upregulation and activation have been established as critical to oncogenesis, the relevant downstream pathways remain incompletely characterized. In this study, we found that c-Jun blocks erythroid differentiation in primary human hematopoietic progenitors and, correspondingly, that Jun factors block transcriptional activation by GATA-1, the central regulator of erythroid differentiation. Mutagenesis of c-Jun suggested that its repression of GATA-1 occurs through a transcriptional mechanism involving activation of downstream genes. We identified the hairy-enhancer-of-split-related factor HERP2 as a novel gene upregulated by c-Jun. HERP2 showed physical interaction with GATA-1 and repressed GATA-1 transcriptional activation. Furthermore, transduction of HERP2 into primary human hematopoietic progenitors inhibited erythroid differentiation. These results thus define a novel regulatory pathway linking the transcription factors c-Jun, HERP2, and GATA-1. Furthermore, these results establish a connection between the Notch signaling pathway, of which the HERP factors are a critical component, and the GATA family, which participates in programming of cellular differentiation.

Antigens, CD34↗
PubMed2003

Wingless and Notch signaling provide cell survival cues and control cell proliferation during wing development.

Tissue growth during animal development depends on the coordination of cell proliferation and cell death. The EGF-receptor/MAPK, Hedgehog, Dpp, Wingless (Wg) and Notch signaling pathways have been implicated in growth control in the developing Drosophila wing. In this report, we examine the effects of Notch and Wg on growth in terms of cell proliferation and cell survival. Reduction of Wg signaling impaired compartment and clonal growth, and increased cell death. Inhibition of apoptosis in cells deficient for Wg signaling only partially rescued the clone growth defect, suggesting that Wg is also required to promote cell proliferation. This is supported by the finding that ectopic expression of Wg caused over-proliferation of cells in the proximal wing. Localized activation of Notch had non-autonomous effects on cell proliferation. However, only part of this effect was attributable to Notch-dependent induction of Wg, suggesting that other Notch-inducible signaling molecules contribute to the control of cell proliferation in the wing.

Animals↗
PubMed1996

A hierarchy of cross-regulation involving Notch, wingless, vestigial and cut organizes the dorsal/ventral axis of the Drosophila wing.

Short-range interaction between dorsal and ventral cells establishes an organizing center at the dorsal/ventral compartment boundary that controls growth and patterning of the wing. We report here that the dorsal/ventral organiser is built though a hierarchy of regulatory interactions involving the Notch and wingless signal transduction pathways and the vestigial gene. wingless and vestigial are activated in cells adjacent to the dorsal/ventral boundary by a Notch-dependent signal. vestigial is initially expressed under control of an early dorsal/ventral boundary enhancer that does not depend on wingless activity. Similarly, activation of wingless does not require vestigial function, showing that wingless and vestigial are parallel targets of the Notch pathway. Subsequently, vestigial is expressed in a broad domain that fills the wing pouch. This second phase of vestigial expression depends on Wingless function in cells at the dorsal/ventral boundary. In addition, the Notch and Wingless pathways act synergistically to regulate expression of cut in cells at the dorsal/ventral boundary. Thus Wingless can act locally, in combination with Notch, to specify cell fates, as well as at a distance to control vestigial expression. These results suggest that secreted Wingless protein mediates both long-range and short-range patterning activities of the dorsal/ventral boundary.

Animals↗
PubMed2002

Notch signaling inhibits PC12 cell neurite outgrowth via RBP-J-dependent and -independent mechanisms.

The Notch signaling pathway has been implicated in the control of neurite extension, although the mechanisms are unknown. In this report, we studied the role of RBP-J/CBF-1 activation, the primary mediator of Notch signaling, in Notch-mediated regulation of neurite outgrowth in PC12 cells. Expression of constitutively active Notch proteins decreased neurite length and number after NGF treatment. In contrast, an inactive Notch protein had no effect on neurite extension. A dominant negative RBP-J construct prevented the reduction of neurite outgrowth by Notch. Conversely, an activated form of RBP-J decreased neurite length but failed to reduce neurite number. In summary, Notch activation inhibited PC12 cell neurite outgrowth by both RBP-J-dependent and -independent pathways.

Animals↗
PubMed1999

Mutations in the heatshock cognate 70 protein (hsc4) modulate Notch signaling.

In our effort to dissect the Notch signaling mechanism we have conducted a screen for mutations that reduce Notch signaling activity. We recovered nine complementation groups as modifiers of the hypomorphic Notch allele notchoid. Apart from the known Notch signaling modulators Notch, Delta and mastermind we isolated alleles in vestigial, wingless, scalloped and clipped, genes known to affect wing morphogenesis. In addition, we identified mutations in Bag, the gene encoding clathrin heavy chain and a dominant mutation of the cytosolic 70 kDa heatshock cognate protein encoded by the hsc4 gene, as Notch signaling modifier. We focused our attention on the latter mutation because it displays dramatic genetic interactions with mutations of the Notch receptor as well as several additional Notch signaling pathway elements. We discuss how hsc4, a gene thought to be involved in subcellular trafficking, may affect the number of functional Notch receptors on the cell surface.

Alleles↗
PubMed2002

Two isoforms of the Notch antagonist Hairless are produced by differential translation initiation.

The Notch-signaling pathway controls cellular differentiation, including proliferation and cell death in all higher metazoans (including flies and men). Signal transduction through activated Notch involves the CSL group of transcriptional regulators. Notch signals need to be tightly regulated, and in Drosophila they are antagonized by the Hairless (H) protein. H silences the activity of Notch target genes by transforming the Drosophila CSL protein, Suppressor of Hairless [Su(H)], from a transcriptional activator into a repressor while recruiting one of the corepressors dCtBP or Groucho. The H protein has a calculated molecular mass of approximately 110 kDa and contains several functional domains apart from the two small corepressor-binding domains. However, although there is no indication for alternative splicing, two Hairless protein isoforms, H(p120) and H(p150), are observed throughout development. Here, we show that the smaller isoform derives from an internal ribosome entry site (IRES) within the ORF. The IRES is active in a heterologous assay and contains an essential, conserved structural element. The two Hairless isoforms have residual activity in vivo which is, however, reduced compared to a combination of both, which implies that both protein isoforms are necessary for WT function. In larval tissues, translation of the two isoforms is cell-cycle regulated: whereas the H(p150) isoform is translated during interphase, H(p120) is enriched during mitosis. Thus, the presence of either H isoform throughout the cell cycle allows efficient inhibition of Notch-regulated cell proliferation.

Animals↗
PubMed2005

Notch: control of lymphocyte differentiation in the periphery.

The complexity of the Notch signalling pathway has impeded progress in understanding its precise role in differentiation processes of the mature peripheral immune system. Nevertheless, both B and T lymphocyte responses are undoubtedly influenced by Notch ligation, and defining the mechanisms by which this is achieved remains a challenge. How the innate-adaptive interface and interactions between lymphocytes can be affected, together with the potential of this pathway for therapeutic intervention remain important and stimulating issues.

Animals↗
PubMed2003

Molecular pathways needed for regeneration of spinal cord and muscle in a vertebrate.

The tail of the frog tadpole, comprising spinal cord, muscle, and notochord, regenerates following partial amputation. We show that, in Xenopus, this occurs throughout development, except for a "refractory period" between stages 45 and 47, when tails heal over without regeneration. Regeneration can be enabled during this refractory period by activation of either the BMP or Notch signaling pathways. Conversely, regeneration can be prevented during the later, regenerative, stages by inhibition of either pathway. BMP signaling will cause regeneration of all tissues, whereas Notch signaling activates regeneration of spinal cord and notochord, but not muscle. An activated form of Msx1 can promote regeneration in the same way as BMP signaling. Epistasis experiments suggest that BMP signaling is upstream of Notch signaling but exerts an independent effect on muscle regeneration. The results demonstrate that regenerative capability can be enabled by genetic modifications that reactivate specific components of the developmental program.

Amputation, Surgical↗
PubMed2006

Methylmercury induces activation of Notch signaling.

Methylmercury (MeHg) toxicity in humans manifests deficits in neurological function. Cases of prenatal exposure to mercury have established that the developing nervous system is most highly susceptible to perturbation by MeHg. At a cellular level, MeHg-induced defects result from altered neuronal proliferation, migration and pathfinding. However, the molecular targets of MeHg that give rise to these outcomes are not fully understood. In an overall effort to identify the fundamental molecular targets of MeHg in neural development, we have explored the effects of MeHg on cell surface receptor function using the simplified Drosophila model. In this study, we investigated the potential role of MeHg to alter activity of the Notch receptor pathway, a highly conserved cell-cell signaling mechanism that controls cell fate decisions, proliferation, migration and neurite outgrowth in neural development. Notch receptor activation requires proteolysis by a cell surface ADAM metalloprotease. ADAM proteases are required for normal neural development and are activated by organomercurials, thus presenting a possible mechanism for MeHg neurotoxicity. Here, we demonstrate a concentration- and time-dependent increase in Notch receptor activity with MeHg exposure in three distinct Drosophila cell lines. Ten micromolar MeHg results in a 4-5.5-fold increase in Notch signaling as measured by the upregulation of two enhancer of split (E(spl)) target genes. MeHg-induced Notch activity also correlates with receptor proteolysis. Targeted knockdown of Notch protein expression demonstrates that MeHg induced E(spl) activation specifically requires the Notch receptor. Furthermore, MeHg-induced Notch activity is partially attenuated by the metalloprotease inhibitor, GM6001, consistent with a model in which MeHg promotes activation of ADAM metalloproteases. Finally, we demonstrate that inorganic HgCl(2) is significantly less active in inducing Notch activity, suggesting a mechanism specific to organic species of mercury. Overall, these data identify Notch as a potential target for MeHg toxicity in the developing nervous system.

Animals↗
PubMed2004

Induction of T-cell development from human cord blood hematopoietic stem cells by Delta-like 1 in vitro.

The Notch signaling pathway plays a key role at several stages of T-lymphocyte differentiation. However, it remained unclear whether signals induced by the Notch ligand Delta-like 1 could support full T-cell differentiation from a defined source of human hematopoietic stem cells (HSCs) in vitro. Here, we show that human cord blood-derived HSCs cultured on Delta-like 1-expressing OP9 stromal cells undergo efficient T-cell lineage commitment and sustained T-cell differentiation. A normal stage-specific program of T-cell development was observed, including the generation of CD4 and CD8 alpha beta-T-cell receptor (TCR)-bearing cells. Induction of T-cell differentiation was dependent on the expression of Delta-like 1 by the OP9 cells. Stimulation of the in vitro-differentiated T cells by TCR engagement induced the expression of T-cell activation markers and costimulatory receptors. These results establish an efficient in vitro coculture system for the generation of T cells from human HSCs, providing a new avenue for the study of early T-cell differentiation and function.

Animals↗
PubMed2006

Notch signaling is inactive but inducible in human embryonic stem cells.

The NOTCH signaling pathway performs a wide range of critical functions in a number of different cell types during development and differentiation. The role of NOTCH signals in human embryonic stem cells (hESCs) has not been tested. We measured the activity of canonical NOTCH signaling in undifferentiated embryonic stem (ES) cells and tested the requirement for NOTCH activity in hESC self-renewal or differentiation by growing hESCs in the presence of gamma-secretase inhibitors. Our results suggest that NOTCH signaling is not required for the propagation of undifferentiated human ES cells but instead is required for the maintenance of the differentiating cell types that accumulate in human ES cell cultures. Our studies suggest that NOTCH signaling is not required in human embryonic differentiation until the formation of extraembryonic, germ layer, or tissue-specific stem cells and progenitors.

Amyloid Precursor Protein Secretases↗
PubMedDate not supplied

Autonomous and non-autonomous regulation of mammalian neurite development by Notch1 and Delta1.

BACKGROUND: On the basis of experiments suggesting that Notch and Delta have a role in axonal development in Drosophila neurons, we studied the ability of components of the Notch signaling pathway to modulate neurite formation in mammalian neuroblastoma cells in vitro. RESULTS: We observed that N2a neuroblastoma cells expressing an activated form of Notch, Notch1(IC), produced shorter neurites compared with controls, whereas N2a cell lines expressing a dominant-negative Notch1 or a dominant-negative Delta1 construct extended longer neurites with a greater number of primary neurites. We then compared the effects on neurites of contacting Delta1 on another cell and of overexpression of Delta1 in the neurite-extending cell itself. We found that N2a cells co-cultured with Delta1-expressing quail cells produced fewer and shorter neuritic processes. On the other hand, high levels of Delta1 expressed in the N2a cells themselves stimulated neurite extension, increased numbers of primary neurites and induced expression of Jagged1 and Notch1. CONCLUSIONS: These studies show that Notch signals can antagonize neurite outgrowth and that repressing endogenous Notch signals enhances neurite outgrowth in neuroblastoma cells. Notch signals therefore act as regulators of neuritic extension in neuroblastoma cells. The response of neuritic processes to Delta1 expressed in the neurite was opposite to that to Delta1 contacted on another cell, however. These results suggest a model in which developing neurons determine their extent of process outgrowth on the basis of the opposing influences on Notch signals of ligands contacted on another cell and ligands expressed in the same cell.

Animals↗
PubMed2004

Dosage-sensitive requirement for mouse Dll4 in artery development.

Involvement of the Notch signaling pathway in vascular development has been demonstrated by both gain- and loss-of-function mutations in humans, mice, and zebrafish. In zebrafish, Notch signaling is required for arterial identity by suppressing the venous fate in developing artery cells. In mice, the Notch4 receptor and the Delta-like 4 (Dll4) ligand are specifically expressed in arterial endothelial cells, suggesting a similar role. Here we show that the Dll4 ligand alone is required in a dosage-sensitive manner for normal arterial patterning in development. This implicates Dll4 as the specific mammalian endothelial ligand for autocrine endothelial Notch signaling, and suggests that Dll4 may be a suitable target for intervention in arterial angiogenesis.

Animals↗
PubMed2004

The Notch target genes Hey1 and Hey2 are required for embryonic vascular development.

The Delta-Notch signaling pathway plays a central role in the development of most vertebrate organs. The Hey family of bHLH transcription factors are direct targets of Notch signaling. Loss of Hey2 in the mouse leads to cardiac defects with high postnatal lethality. We have now generated a mouse Hey1 knockout that has no apparent phenotypic defect. The combined loss of Hey1 and Hey2, however, results in embryonic death after embryonic day 9.5 (E9.5) with a global lack of vascular remodeling and massive hemorrhage. Initial vasculogenesis appears unaffected, but all subsequently developing major vessels in the embryo and yolk sac are either small or absent. Furthermore, the placental labyrinth completely lacks embryonic blood vessels. Similar vascular defects are observed in Jagged1 and Notch1 knockout mice. In the latter we found Hey1 and Hey2 expression in yolk sacs to be strongly reduced. Remaining large arteries in both Notch1 and Hey1/Hey2 knockout mice fail to express the arterial endothelial markers CD44, neuropilin1, and ephrin-B2. This indicates that Hey1/Hey2 are essential transducers of Notch signals in cardiovascular development that may mediate arterial cell fate decision.

Animals↗
PubMed2006

Notch activity is downregulated just prior to retinal ganglion cell differentiation.

The Notch signaling pathway is important at several stages of retinal development including the differentiation of retinal ganglion cells and Muller glia. The downstream effectors of Notch signaling, Hes1 and Hes5, have been shown to be critical in the retina as well. While Notch activity directly regulates Hes1 and Hes5 elsewhere in the nervous system, it has been unclear whether Hes1 and/or Hes5 are directly regulated by Notch activity in the developing retina. Here, we report that both Hes1 and Hes5 are directly regulated by Notch activity during retinal development. Using fluorescence-based Hes1 and Hes5 reporter constructs, we can monitor Notch activity in progenitor cells in the intact retina, and we find that Notch activity is downregulated just prior to retinal ganglion cell differentiation.

Amino Acid Sequence↗
PubMed2005

The Notch targets Esr1 and Esr10 are differentially regulated in Xenopus neural precursors.

The HES family of bHLH repressors plays a key role in regulating the differentiation of neural precursors in the vertebrate embryo. Members of the HES gene family are expressed in neural precursors as targets of the Notch signaling pathway, but how this occurs in the context of neurogenesis is not known. Here, we address this issue by identifying enhancers driving Notch-dependent gene expression of two Hes5-like genes expressed in Xenopus called Esr1 and Esr10. Using frog transgenesis, we identify enhancer elements driving expression of Esr1 and Esr10 in neural precursors or in response to ectopic expression of the proneural protein, Xngnr1. Using deletion and mutation analysis, we define motifs required for enhancer activity of both genes, namely Notch-responsive elements and, in the case of Esr10, E-box motifs. We find that Esr1 and Esr10 are differentially regulated both in terms of Notch input and its interaction with heterologous factors. These studies reveal inputs required for proneural expression of genes encoding bHLH repressors in the developing vertebrate nervous system.

Animals↗
PubMed2005

Tsukushi controls ectodermal patterning and neural crest specification in Xenopus by direct regulation of BMP4 and X-delta-1 activity.

In Xenopus, ectodermal patterning depends on a mediolateral gradient of BMP signaling, higher in the epidermis and lower in the neuroectoderm. Neural crest cells are specified at the border between the neural plate and the epidermis, at intermediate levels of BMP signaling. We recently described a novel secreted protein, Tsukushi (TSK), which works as a BMP antagonist during chick gastrulation. Here, we report on the Xenopus TSK gene (X-TSK), and show that it is involved in neural crest specification. X-TSK expression accumulates after gastrulation at the anterior-lateral edges of the neural plate, including the presumptive neural crest region. In gain-of-function experiments, X-TSK can strongly enhance neural crest specification by the dorsolateral mesoderm or X-Wnt8 in ectodermal explants, while the electroporation of X-TSK mRNA in the lateral ectoderm of embryos after gastrulation can induce the expression of neural crest markers in vivo. By contrast, depletion of X-TSK in explants or embryos impairs neural crest specification. Similarly to its chick homolog, X-TSK works as a BMP antagonist by direct binding to BMP4. However, X-TSK can also indirectly regulate BMP4 mRNA expression at the neural plate border via modulation of the Delta-Notch signaling pathway. We show that X-TSK directly binds to the extracellular region of X-delta-1, and modulates Delta-dependent Notch activity. We propose that X-TSK plays a key role in neural crest formation by directly regulating BMP and Delta activities at the boundary between the neural and the non-neural ectoderm.

Animals↗