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PubMed1994

A member of the Notch group of interacting loci, deltex encodes a cytoplasmic basic protein.

Prior genetic studies have suggested a functional relationship between the product of the deltex gene and those of three of the so-called "neurogenic" loci, Notch, Delta and mastermind. To gain further insight into this relationship, we have proceeded with a molecular characterization of deltex. We report that deltex encodes a maternally and zygotically expressed transcript that conceptually translates to a basic protein of novel sequence. Immunolocalization of the protein reveals an apparently ubiquitous distribution in embryonic and imaginal tissues. Because our detection methods also reveal a very low level of protein accumulation within the cytoplasm of cells, we have used transgenic flies to confirm this observation by ectopically expressing deltex under the control of a heat shock gene promoter. The resulting overexpression rescues deltex mutant defects but does not produce any obvious phenotypic abnormalities in otherwise wild-type flies. Finally, we examine genetically several Supressor of deltex mutations for evidence of functional integration with deltex and other neurogenic genes. We demonstrate that in addition to suppressing all adult morphological defects of deltex alleles, these suppressors also are capable of suppressing most synergistic effects involving deltex and Notch, Delta and mastermind.

Amino Acid Sequence↗
PubMed1997

Dominant enhancers of Egfr in Drosophila melanogaster: genetic links between the Notch and Egfr signaling pathways.

The Drosophila epidermal growth factor receptor (EGFR) is a key component of a complex signaling pathway that participates in multiple developmental processes. We have performed an F1 screen for mutations that cause dominant enhancement of wing vein phenotypes associated with mutations in Egfr. With this screen, we have recovered mutations in Hairless (H), vein, groucho (gro), and three apparently novel loci. All of the E(Egfr)s we have identified show dominant interactions in transheterozygous combinations with each other and with alleles of N or Su(H), suggesting that they are involved in cross-talk between the N and EGFR signaling pathways. Further examination of the phenotypic interactions between Egfr, H, and gro revealed that reductions in Egfr activity enhanced both the bristle loss associated with H mutations, and the bristle hyperplasia and ocellar hypertrophy associated with gro mutations. Double mutant combinations of Egfr and gro hypomorphic alleles led to the formation of ectopic compound eyes in a dosage sensitive manner. Our findings suggest that these E(Egfr)s represent links between the Egfr and Notch signaling pathways, and that Egfr activity can either promote or suppress Notch signaling, depending on its developmental context.

Animals↗
PubMed1999

Embryonic lethality and vascular defects in mice lacking the Notch ligand Jagged1.

The Notch signaling pathway is an evolutionarily conserved intercellular signaling mechanism essential for embryonic development in mammals. Mutations in the human JAGGED1 ( JAG1 ) gene, which encodes a ligand for the Notch family of transmembrane receptors, cause the autosomal dominant disorder Alagille syndrome. We have examined the in vivo role of the mouse Jag1 gene by creating a null allele through gene targeting. Mice homozygous for the Jag1 mutation die from hemorrhage early during embryogenesis, exhibiting defects in remodeling of the embryonic and yolk sac vasculature. We mapped the Jag1 gene to mouse chromosome 2, in the vicinity of the Coloboma ( Cm ) deletion. Molecular and complementation analyses revealed that the Jag1 gene is functionally deleted in the Cm mutant allele. Mice heterozygous for the Jag1 null allele exhibit an eye dysmorphology similar to that of Cm /+ heterozygotes, but do not exhibit other phenotypes characteristic of Cm /+ mice or of humans with Alagille syndrome. These results establish the phenotype of Cm /+ mice as a contiguous gene deletion syndrome and demonstrate that Jag1 is essential for remodeling of the embryonic vasculature.

Animals↗
PubMed2003

Notch signaling and inherited disease syndromes.

The Notch signaling pathway is an evolutionarily conserved, intercellular signaling mechanism essential for proper embryonic development in organisms as diverse as insects, nematodes, echinoderms and mammals. Disruptions in conserved developmental pathways frequently result in inherited congenital anomalies in humans. Mutations in genes encoding Notch pathway components underlie three inherited human diseases: Alagille syndrome, spondylocostal dysostosis, and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. Mouse models for these three diseases have been developed, and are leading to novel insights into the pathology of these diseases in humans.

Alagille Syndrome↗
PubMed2005

Epithelial differentiation in pancreatic development and neoplasia: new niches for nestin and Notch.

Changes in epithelial differentiation represent a characteristic early feature of human pancreatic cancer. Recent work suggests that many of these changes may reflect a pathologic recapitulation of developmental events. Reflecting this principle, metaplastic and neoplastic pancreatic epithelium appear to share many features in common with embryonic pancreatic epithelium, including reactivation of the Notch signaling pathway. In this review, we summarize recent studies involving regulation of epithelial differentiation in both embryonic and adult pancreas and highlight the role of Notch in regulating an exocrine progenitor pool.

Animals↗
PubMed1998

Ligand-induced cleavage and regulation of nuclear entry of Notch in Drosophila melanogaster embryos.

Notch, a transmembrane protein found in a wide range of organisms, is a component of a pathway that mediates cell-fate decisions that involve intercellular communication. In this paper, we show that in Drosophila melanogaster, Notch (N) is processed in a ligand-dependent fashion to generate phosphorylated, soluble intracellular derivatives. Suppressor of Hairless [Su(H)] is predominantly associated with soluble intracellular N. It has been demonstrated by others that N has access to the nucleus, and we show that when tethered directly to DNA, the cytoplasmic domain of N can activate transcription. Conversely, a viral activator fused to Su(H) can substitute for at least some N functions during embryogenesis. We suggest that one function of soluble forms of N is to bind to Su(H), and in the nucleus, to act directly as a transcriptional transactivator of the latter protein. Although N has functional nuclear localization signals, the N/Su(H) complex accumulates in the cytoplasm and on membranes suggesting that its nuclear entry is regulated. Localization studies in cultured cells and embryos suggest that Su(H) plays a role in this regulation, with the relative levels of Delta, N and Su(H) determining whether a N/Su(H) complex enters the nucleus.

Animals↗
PubMed2004

Primitive neural stem cells from the mammalian epiblast differentiate to definitive neural stem cells under the control of Notch signaling.

Basic fibroblast growth factor (FGF2)-responsive definitive neural stem cells first appear in embryonic day 8.5 (E8.5) mouse embryos, but not in earlier embryos, although neural tissue exists at E7.5. Here, we demonstrate that leukemia inhibitory factor-dependent (but not FGF2-dependent) sphere-forming cells are present in the earlier (E5.5-E7.5) mouse embryo. The resultant clonal sphere cells possess self-renewal capacity and neural multipotentiality, cardinal features of the neural stem cell. However, they also retain some nonneural properties, suggesting that they are the in vivo cells' equivalent of the primitive neural stem cells that form in vitro from embryonic stem cells. The generation of the in vivo primitive neural stem cell was independent of Notch signaling, but the activation of the Notch pathway was important for the transition from the primitive to full definitive neural stem cell properties and for the maintenance of the definitive neural stem cell state.

Animals↗
PubMed2001

Activation of the Notch-regulated transcription factor CBF1/RBP-Jkappa through the 13SE1A oncoprotein.

Signaling through the Notch pathway controls cell growth and differentiation in metazoans. Following binding of its ligands, the intracellular part of the cell surface Notch1 receptor (Notch1-IC) is released and translocates to the nucleus, where it alters the function of the DNA-binding transcription factor CBF1/RBP-Jkappa. As a result, CBF1/RBP-Jkappa is converted from a repressor to an activator of gene transcription. Similarly, the Epstein Barr viral oncoprotein EBNA2, which is required for B-cell immortalization, activates genes through CBF1. Moreover, the TAN-1 and int-3 oncogenes represent activated versions of Notch1 and Notch4, respectively. Here, we show that the adenoviral oncoprotein 13S E1A also binds to CBF1/RBP-Jkappa, displaces associated corepressor complexes, and activates CBF1/RBP-Jkappa-dependent gene expression. Our results suggest that the central role of the Notch-CBF1/RBP-Jkappa signaling pathway in cell fate decisions renders it susceptible to pathways of viral replication and oncogenic conversion.

Adenovirus E1A Proteins↗
PubMed1995

canoe encodes a novel protein containing a GLGF/DHR motif and functions with Notch and scabrous in common developmental pathways in Drosophila.

The canoemisty1 (cnomis1) mutation was isolated by virtue of its severe rough eye phenotype from approximately 500 fly lines, each harboring a single autosomal insertion of a P element (Bm delta w). Excision of the P element generated a lethal, null allele, cnomis10, together with many revertants with normal eye morphology. Ommatidia homozygous for cnomis10, produced in an otherwise wild-type eye by somatic recombination, typically contain a reduced number of outer photoreceptors. Some cnomis1 homozygous adults bear extra macrochaetes on the head, notum, humerus and/or scutellum. cnomis1 hemizygotes often show conspicuous wing phenotypes such as a notched blade and the loss of a cross vein. The sequence of cno cDNA clones isolated from an embryonic cDNA library revealed a long open reading frame that potentially encodes a 1893-amino-acid protein with the GLGF/DHR motif, a conserved sequence in Discs large, Dishevelled, and some other proteins associated with cellular junctions. Flies doubly mutant for cnomis1 and scabrous1 (sca1) and those for cnomis1 and the split (spl) allele of Notch (N) always have rumpled wings curved downward. The spl; cnomis1 double mutant flies also exhibit a "giant socket" phenotype. These phenotypes are rarely observed flies singly mutant for either cnomis1, sca1 or spl. The wing vein gaps caused by Abruptex1, a N allele producing an activated form of N protein, are dominantly suppressed by cnomis1. Heterozygosity for shaggy and myospheroid promotes formation of extra wing veins in cnomis1 homozygotes. The genetic interactions suggest that cno participates with members of the N pathway in regulating adhesive cell-cell interactions for the determination of cell fate.

Amino Acid Sequence↗
PubMed2006

TCR and Notch signaling in CD4 and CD8 T-cell development.

The generation of CD4 and CD8 alphabeta T-cell lineages from CD4+ CD8+ double-positive (DP) thymocyte precursors is a complex process initiated by engagement of major histocompatibility complex (MHC) by T-cell receptor (TCR) and coreceptor. Quantitative differences in TCR signaling induced by this interaction impose an instructional bias on CD4/CD8 lineage commitment that must be reinforced by MHC recognition and TCR signaling over subsequent selection steps in order for the thymocyte to progress and mature in the adopted lineage. Our studies show that the transmembrane receptor Notch plays a role in this process by modifying TCR signal transduction in DP thymocytes. In this review, we consider the functional relationship of TCR and Notch signaling pathways in the selection and specification of CD4 and CD8 T-cell lineages.

Animals↗
PubMed2004

Microglia release activators of neuronal proliferation mediated by activation of mitogen-activated protein kinase, phosphatidylinositol-3-kinase/Akt and delta-Notch signalling cascades.

Microglia, the resident macrophage of the brain, can release substances that aid neuronal development, differentiation and survival. We have investigated the effects of non-activated microglia on the survival of cultured rat cerebellar granule neurones. Microglial-conditioned medium, collected from primary rat microglial cultures, was used to treat 7-day-in-vitro neurones, and neuronal viability and proliferation was assessed following a further 1 or 7 days in culture. Microglial-conditioned medium enhanced neuronal survival by up to 50% compared with untreated neurones and this effect was completely abated by pretreatment of the microglia with l-leucine methyl ester. The expression of the proliferation marker Ki-67 increased in neuronal cultures treated with microglial-conditioned medium suggesting enhanced proliferation of precursor neurones. Microglial-induced neuronal proliferation could be attenuated by specific inhibition of mitogen-activated protein kinase or phosphatidylinositol-3-kinase/Akt signalling pathways, and by selective fractionation and immunodepletion of the microglial-conditioned medium. Activation of the Notch pathway was enhanced as antibody against the Notch ligand, delta-1, prevented the microglial-induced neuronal proliferation. These results show that microglia release stable neurotrophic factors that can promote neuronal precursor cell proliferation.

Animals↗
PubMed2006

The novel gamma secretase inhibitor N-[cis-4-[(4-chlorophenyl)sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) reduces amyloid plaque deposition without evidence of notch-related pathology in the Tg2576 mouse.

There is a substantial body of evidence indicating that beta-amyloid peptides (Abeta) are critical factors in the onset and development of Alzheimer's disease (AD). One strategy for combating AD is to reduce or eliminate the production of Abeta through inhibition of the gamma-secretase enzyme, which cleaves Abeta from the amyloid precursor protein (APP). We demonstrate here that chronic treatment for 3 months with 3 mg/kg of the potent, orally bioavailable and brain-penetrant gamma-secretase inhibitor N-[cis-4-[(4-chlorophenyl)-sulfonyl]-4-(2,5-difluorophenyl)cyclohexyl]-1,1,1-trifluoromethanesulfonamide (MRK-560) attenuates the appearance of amyloid plaques in the Tg2576 mouse. These reductions in plaques were also accompanied by a decrease in the level of reactive gliosis. The morphometric and histological measures agreed with biochemical analysis of Abeta(40) and Abeta(42) in the cortex. Interestingly, the volume of the plaques across treatment groups did not change, indicating that reducing Abeta levels does not significantly alter deposit growth once initiated. Furthermore, we demonstrate that these beneficial effects can be achieved without causing histopathological changes in the ileum, spleen, or thymus as a consequence of blockade of the processing of alternative substrates, such as the Notch family of receptors. This indicates that in vivo a therapeutic window between these substrates seems possible--a key concern in the development of this approach to AD. An understanding of the mechanisms whereby MRK-560 shows differentiation between the APP and Notch proteolytic pathway of gamma-secretase should provide the basis for the next generation of gamma-secretase inhibitors.

Alzheimer Disease↗
PubMed2004

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

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

Cloning, Molecular↗
PubMed2004

Notch-induced E2A degradation requires CHIP and Hsc70 as novel facilitators of ubiquitination.

E2A transcription factors, E12 and E47, are important regulators of lymphocyte development. Notch signaling pathways have been shown to regulate E2A function by accelerating the degradation of E2A proteins through a mitogen-activated protein kinase-dependent and ubiquitin-mediated pathway. To further understand the mechanism underlying E2A ubiquitination and degradation, we conducted a yeast two-hybrid screen and identified the carboxyl terminus of Hsc70-interacting protein (CHIP) as an E47 binding protein. Here, we show that CHIP associates with E2A proteins in vivo and that overexpression of CHIP induces E47 degradation in a phosphorylation-dependent manner. Conversely, knocking down CHIP with small interfering RNA alleviates Notch-induced E47 degradation. CHIP binds E47 through the E protein homology domains 2 and 3 (EHD2 and EHD3). This interaction between CHIP and E47 is independent of the U-box domain with E3 ubiquitin ligase activity but requires the chaperone binding tetratricopeptide repeats domain. The ability of CHIP to induce E47 ubiquitination and degradation correlates with its ability to bind E47. We propose that CHIP, together with its partner Hsc70, forms a preubiquitination complex (PUC) with E47 and Skp2, thus facilitating the interaction between E47 and Skp2. CHIP also associates with Cul1, which introduces PUC to the SCF E3 ligase complex, responsible for E47 ubiquitination. Therefore, CHIP plays a crucial role in the ubiquitination and degradation of E2A proteins.

Amino Acid Sequence↗
PubMed2006

Functional arterial and venous fate is determined by graded VEGF signaling and notch status during embryonic stem cell differentiation.

OBJECTIVE: The aim of this work was to develop a mouse embryonic stem (ES) cell system addressing the early specification of the developing vasculature into functional arteries and veins. METHODS AND RESULTS: ES cells were differentiated 4 days on collagen-type IV coated dishes to obtain Flk1+ endothelial precursors. Sub-culture of these precursors for additional 4 days robustly generated, in a VEGF dose-dependent manner, mature endothelial cells. Arterial marker genes were specifically expressed in cultures differentiated with high VEGF concentration whereas the venous marker gene COUP-TFII was upregulated in endothelial cells induced through low and intermediate VEGF concentrations. This VEGF-dependent arterialization could be blocked by inhibition of Notch resulting in an arterial to venous fate switch. Functional and morphological studies, ie, measurement of sprout length, pericyte recruitment, and interleukin-I-induced leukocyte adhesion, further confirmed their arterial and venous identity. CONCLUSIONS: We conclude that endothelial cells with distinct molecular, morphological, and functional characteristics of arteries and veins can be derived through in vitro differentiation of ES cells in a VEGF dose-dependent and Notch-regulated manner.

Animals↗
PubMed2004

Jagged1-dependent Notch signaling is dispensable for hematopoietic stem cell self-renewal and differentiation.

Jagged1-mediated Notch signaling has been suggested to be critically involved in hematopoietic stem cell (HSC) self-renewal. Unexpectedly, we report here that inducible Cre-loxP-mediated inactivation of the Jagged1 gene in bone marrow progenitors and/or bone marrow (BM) stromal cells does not impair HSC self-renewal or differentiation in all blood lineages. Mice with simultaneous inactivation of Jagged1 and Notch1 in the BM compartment survived normally following a 5FU-based in vivo challenge. In addition, Notch1-deficient HSCs were able to reconstitute mice with inactivated Jagged1 in the BM stroma even under competitive conditions. In contrast to earlier reports, these data exclude an essential role for Jagged1-mediated Notch signaling during hematopoiesis.

Animals↗
PubMed2004

Notch ligands Delta 1 and Jagged1 transmit distinct signals to T-cell precursors.

Signaling through the Notch pathway plays an essential role in inducing T-lineage commitment and promoting the maturation of immature thymocytes. Using an in vitro culture system, we show that 2 different classes of Notch ligands, Jagged1 or Delta1, transmit distinct signals to T-cell progenitors. OP9 stromal cells expressing either Jagged1 or Delta1 inhibit the differentiation of DN1 thymocytes into the B-cell lineage, but only the Delta1-expressing stromal cells promote the proliferation and maturation of T-cell progenitors through the early double-negative (DN) stages of thymocyte development. Whereas the majority of bone marrow-derived stem cells do not respond to Jagged1 signals, T-cell progenitors respond to Jagged1 signals during a brief window of their development between the DN1 and DN3 stages of thymic development. During these stages, Jagged1 signals can influence the differentiation of immature thymocytes along the natural killer (NK) and gamma delta T-cell lineages.

Animals↗
PubMed2006

Notch-dependent T-lineage commitment occurs at extrathymic sites following bone marrow transplantation.

Early T-lineage progenitors (ETPs) arise after colonization of the thymus by multipotent bone marrow progenitors. ETPs likely serve as physiologic progenitors of T-cell development in adult mice, although alternative T-cell differentiation pathways may exist. While we were investigating mechanisms of T-cell reconstitution after bone marrow transplantation (BMT), we found that efficient donor-derived thymopoiesis occurred before the pool of ETPs had been replenished. Simultaneously, T lineage-restricted progenitors were generated at extrathymic sites, both in the spleen and in peripheral lymph nodes, but not in the bone marrow or liver. The generation of these T lineage-committed cells occurred through a Notch-dependent differentiation process. Multipotent bone marrow progenitors efficiently gave rise to extrathymic T lineage-committed cells, whereas common lymphoid progenitors did not. Our data show plasticity of T-lineage commitment sites in the post-BMT environment and indicate that Notch-driven extrathymic Tlineage commitment from multipotent progenitors may contribute to early T-lineage reconstitution after BMT.

Animals↗