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PubMed2002

SHARP is a novel component of the Notch/RBP-Jkappa signalling pathway.

Notch proteins are the receptors for an evolutionarily highly conserved signalling pathway that regulates numerous cell fate decisions during development. Signal transduction involves the presenilin-dependent intracellular processing of Notch and nuclear translocation of the intracellular domain of Notch, Notch-IC. Notch-IC associates with the DNA-binding protein RBP-Jkappa/CBF-1 to activate transcription of Notch target genes. In the absence of Notch signalling, RBP-Jkappa/CBF-1 acts as a transcriptional repressor through the recruitment of histone deacetylase (HDAC) corepressor complexes. We identified SHARP as an RBP-Jkappa/CBF-1-interacting corepressor in a yeast two-hybrid screen. In cotransfection experiments, SHARP-mediated repression was sensitive to the HDAC inhibitor TSA and facilitated by SKIP, a highly conserved SMRT and RBP-Jkappa-interacting protein. SHARP repressed Hairy/Enhancer of split (HES)-1 promoter activity, inhibited Notch-1-mediated transactivation and rescued Notch-1-induced inhibition of primary neurogenesis in Xenopus laevis embryos. Based on our data, we propose a model in which SHARP is a novel component of the HDAC corepressor complex, recruited by RBP-Jkappa to repress transcription of target genes in the absence of activated Notch.

Adaptor Proteins, Signal Transducing↗
PubMed2006

Transcriptional profiling implicates TGFbeta/BMP and Notch signaling pathways in ductular differentiation of fetal murine hepatoblasts.

Bile duct morphogenesis involves sequential induction of biliary specific gene expression, bilayer generation, cell proliferation, remodeling and apoptosis. HBC-3 cells are a model system to study differentiation of hepatoblasts along the hepatocytic or bile ductular lineage in vitro and in vivo. We used microarray to define molecular pathways during ductular differentiation in response to Matrigel. The temporal pattern of expression of marker genes induced was similar to that observed during bile duct formation in vivo. Notch, HNF1beta, Polycystic kidney disease 2, Bicaudal C 1 and beta-catenin were up regulated during the time course. Functional clustering analysis revealed significant up regulation of clusters of genes involved in extracellular matrix remodeling, ion transport, vacuoles, lytic vacuoles, pro-apoptotic and anti-apoptotic genes, transcription factors and negative regulators of the cell proliferation, while genes involved in the cell cycle were significantly down regulated. Notch signaling pathway was activated by treatment with Matrigel. In addition, TGFbeta/BMP signaling pathway members including the type I TGFbeta receptor and Smads 3, 4 and 5 were significantly up regulated, as were several TGFbeta/BMP responsive genes including Hey 1, a regulator of Notch pathway signaling. SMADS 3, 4 and 5 were present in the nuclear fraction of HBC-3 cells during ductular differentiation in vitro, but not during hepatocyte differentiation. SMAD 5 was preferentially expressed in hepatoblasts undergoing bile duct morphogenesis in the fetal liver, while the TGFbeta/BMP signaling antagonist chordin, was expressed throughout the liver suggesting a mechanism by which TGFbeta/BMP signaling is limited to hepatoblasts that contact portal mesenchyme in vivo.

Animals↗
PubMed1999

Interaction between Notch signalling and Lunatic fringe during somite boundary formation in the mouse.

BACKGROUND: The process of somitogenesis can be divided into three major events: the prepatterning of the mesoderm; the formation of boundaries between the prospective somites; and the cellular differentiation of the somites. Expression and functional studies have demonstrated the involvement of the murine Notch pathway in somitogenesis, although its precise role in this process is not yet well understood. We examined the effect of mutations in the Notch pathway elements Delta like 1 (Dll1), Notch1 and RBPJkappa on genes expressed in the presomitic mesoderm (PSM) and have defined the spatial relationships of Notch pathway gene expression in this region. RESULTS: We have shown that expression of Notch pathway genes in the PSM overlaps in the region where the boundary between the posterior and anterior halves of two consecutive somites will form. The Dll1, Notch1 and RBPJkappa mutations disrupt the expression of Lunatic fringe (L-fng), Jagged1, Mesp1, Mesp2 and Hes5 in the PSM. Furthermore, expression of EphA4, mCer 1 and uncx4.1, markers for the anterior-posterior subdivisions of the somites, is down-regulated to different extents in Notch pathway mutants, indicating a global alteration of pattern in the PSM. CONCLUSIONS: We propose a model for the mechanism of somite border formation in which the activity of Notch in the PSM is restricted by L-fng to a boundary-forming territory in the posterior half of the prospective somite. In this region, Notch function activates a set of genes that are involved in boundary formation and anterior-posterior somite identity.

Animals↗
PubMed2005

Meningioma transcript profiles reveal deregulated Notch signaling pathway.

Meningiomas constitute the second most common central nervous system tumor, and yet relatively little is known about the molecular events that are important for the pathogenesis and malignant progression of these tumors. We have used serial analysis of gene expression to compare the transcriptomes of nonneoplastic meninges and meningiomas of all malignancy grades. A novel finding from this screen is the induction of three components of the Notch signaling pathway: the transcription factor, hairy and enhancer of Split1 (HES1) and two members of the Groucho/transducin-like enhancer of Split family of corepressors, TLE2 and TLE3. TLE corepressors interact and modulate the activity of a wide range of transcriptional regulatory systems, one of which is HES1. We have shown that the transcript and protein levels of HES1, the Notch2 and Notch1 receptors and the Jagged1 ligand are induced in meningiomas of all grades, whereas induction of TLE2 and TLE3 occurs specifically in higher-grade meningiomas. Meningioma cell lines express components of the Notch signaling pathway and an inhibitor of this pathway suppresses meningioma cell survival. These results suggest that deregulated expression of the Notch pathway is a critical event in meningioma pathogenesis and that modulation of this and potentially other signaling pathways by TLE corepressors leads to a more malignant phenotype.

Basic Helix-Loop-Helix Proteins↗
PubMed2003

Feedback loops comprising Dll1, Dll3 and Mesp2, and differential involvement of Psen1 are essential for rostrocaudal patterning of somites.

Elaborate metamerism in vertebrate somitogenesis is based on segmental gene expression in the anterior presomitic mesoderm (PSM). Notch signal pathways with Notch ligands Dll1 and Dll3, and the transcription factor Mesp2 are implicated in the rostrocaudal patterning of the somite. We have previously shown that changes in the Mesp2 expression domain from a presumptive one somite into a rostral half somite results in differential activation of two types of Notch pathways, dependent or independent of presenilin 1 (Psen1), which is a Notch signal mediator. To further refine our hypothesis, we have analyzed genetic interactions between Dll1, Dll3, Mesp2 and Psen1, and elucidated the roles of Dll1- and Dll3-Notch pathways, with or without Psen1, in rostrocaudal patterning. Dll1 and Dll3 are co-expressed in the PSM and so far are considered to have partially redundant functions. We find in this study that positive and negative feedback loops comprising Dll1 and Mesp2 appear to be crucial for this patterning, and Dll3 may be required for the coordination of the Dll1-Mesp2 loop. Additionally, our epistatic analysis revealed that Mesp2 affects rostrocaudal properties more directly than Dll1 or Dll3. Finally, we find that Psen1 is involved differently in the regulation of rostral and caudal genes. Psen1 is required for Dll1-Notch signaling for activation of Dll1, while the Psen1-independent Dll3-Notch pathway may counteract the Psen1-dependent Dll1-Notch pathway. These observations suggest that Dll1 and Dll3 may have non-redundant, even counteracting functions. We conclude from our analyses that Mesp2 functions as a central mediator of such Notch pathways and regulates the gene expression required for rostrocaudal patterning of somites.

Animals↗
PubMed1996

The intracellular deletions of Delta and Serrate define dominant negative forms of the Drosophila Notch ligands.

We examined the function of the intracellular domains of the two known Drosophila Notch ligands, Delta and Serrate, by expressing wild-type and mutant forms in the developing Drosophila eye under the sevenless promoter. The expression of intracellularly truncated forms of either Delta (sev-DlTM) or Serrate (sev-SerTM) leads to extra photoreceptor phenotypes, similar to the eye phenotypes associated with loss-of-function mutations of either Notch or Delta. Consistent with the notion that the truncated ligands reduce. Notch signalling activity, the eye phenotypes of sev-DlTM and sev-SerTM are enhanced by loss-of-function mutations in the Notch pathway elements, Notch, Delta, mastermind, deltex and groucho, but are suppressed by a duplication of Delta or mutations in Hairless, a negative regulator of the pathway. These observations were extended to the molecular level by demonstrating that the expression of Enhancer of split m delta, a target of Notch signalling, is down-regulated by the truncated ligands highly expressed in neighbouring cells. We conclude that the truncated ligands act as antagonists of Notch signalling.

Amino Acid Sequence↗
PubMed2005

Human SRCAP and Drosophila melanogaster DOM are homologs that function in the notch signaling pathway.

The putative ATPase chromatin-remodeling machine SRCAP was identified in a yeast two-hybrid protein screen by interaction with the histone acetylase CBP. SRCAP is implicated in the transcriptional coactivation of cyclic AMP- and steroid-dependent promoters, but no natural chromosomal targets for SRCAP regulation have been identified. DOM is the unique SRCAP homolog in Drosophila melanogaster. The goal of this study was to test whether SRCAP is a functional homolog of DOM and to identify potential activities and targets of SRCAP in vivo. We show that human SRCAP complements recessive domino mutant phenotypes. This rescue depends on an intact ATPase homology domain. SRCAP colocalizes extensively with DOM on Drosophila polytene chromosomes and is recruited to sites of active transcription, such as steroid-regulated loci, but not to activated heat shock loci. We show that SRCAP recruits Drosophila CBP to ectopic chromosomal sites, providing the first evidence to suggest that SRCAP and CBP interact directly or indirectly on chromosomes. We show that DOM is a Notch pathway activator in Drosophila and that wild-type SRCAP-but not an ATPase domain mutant-can substitute for DOM in Notch-dependent wing development. We show that SRCAP potentiates Notch-dependent gene activation in HeLa cells. Taken together, these data implicate SRCAP and DOM in developmental gene activation.

Adenosine Triphosphatases↗
PubMed2003

Activation of Notch signaling pathway precedes heart regeneration in zebrafish.

Several vertebrates display the ability to regenerate parts of their body after amputation. During this process, differentiated cells reenter the cell cycle and proliferate to generate a mass of undifferentiated cells. Repatterning mechanisms act on these cells to eventually shape a regenerated tissue or organ that replaces the amputated one. Experiments with regenerating limbs/fins in newts and zebrafish have shown that members of the Msx family of homeodomain-containing transcription factors play key roles during blastema formation and patterning. Here we show that adult zebrafish have a remarkable capacity to regenerate the heart in a process that involves up-regulation of msxB and msxC genes. We present evidence indicating that heart regeneration involves the execution of a specific genetic program, rather than redeployment of a cardiac development program. Preceding Msx activation, there is a marked increase in the expression of notch1b and deltaC, which we show are also up-regulated during fin regeneration. These data suggest a role for the Notch pathway in the activation of the regenerative response. Taken together, our results underscore the use of zebrafish as a model for investigating the process of regeneration in particular and the biology of stem cells in general. Advances in these fields will undoubtedly aid in the implementation of strategies for regenerative medicine.

Animals↗
PubMed2002

The lytic switch protein of KSHV activates gene expression via functional interaction with RBP-Jkappa (CSL), the target of the Notch signaling pathway.

The RTA protein of the Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is responsible for the switch from latency to lytic replication, a reaction essential for viral spread and KS pathogenesis. RTA is a sequence-specific transcriptional activator, but the diversity of its target sites suggests it may act via interaction with host DNA-binding proteins as well. Here we show that KSHV RTA interacts with the RBP-Jkappa protein, the primary target of the Notch signaling pathway. This interaction targets RTA to RBP-Jkappa recognition sites on DNA and results in the replacement of RBP-Jkappa's intrinsic repressive action with activation mediated by the C-terminal domain of RTA. Mutation of such sites in target promoters strongly impairs RTA responsiveness. Similarly, such target genes are induced poorly or not at all by RTA in fibroblasts derived from RBP-Jkappa(-/-) mice, a defect that can be reversed by expression of RBP-Jkappa. In vitro, RTA binds to two adjacent regions of RBP-Jkappa, one of which is identical to the central repression domain that binds the Notch effector fragment. These results indicate that KSHV has evolved a ligand-independent mechanism for constitutive activation of the Notch pathway as a part of its strategy for reactivation from latency.

Animals↗
PubMed2004

Coexpression of Cux-1 and Notch signaling pathway components during kidney development.

Cux-1 is the murine homologue of the Drosophila gene cut, which is required for cellular differentiation in several tissues, including the wing margin and Malpighian tubule. Mammalian cut proteins function as cell cycle-dependent transcriptional repressors in proliferating cells. Targets of Cux-1 repression include the cyclin kinase inhibitors p21 and p27. However, little is known about the regulation of Cux-1. In Drosophila, multiple genetic interactions between Cut and the Notch and Wingless signaling pathways occur during wing development. To begin to determine whether Cux-1 regulation by the Notch signaling pathway is conserved in mammals, we compared the expression patterns of Cux-1, the murine Notch receptors (Notch 1-4), and the murine ligands (Jagged 1, Jagged 2, and Delta 1) during murine embryogenesis and kidney development. In this report, we demonstrate that Cux-1 expression overlaps with that of Notch signaling pathway components in multiple tissues during embryonic development. In the developing kidney, Cux-1 expression overlaps with that of Notch pathway components in the condensing mesenchyme, in pretubular aggregates (comma and S-shaped bodies), and in the presumptive podocytes of capillary loop stage glomeruli. Furthermore, Cux-1 was significantly up-regulated in the rat kidney epithelial cell line RKE expressing a constitutively active Notch 1, and this finding was associated with a reduction of p27. Moreover, Cux-1 interacts with the Groucho homolog TLE-4, a corepressor recruited by Notch effector proteins. Taken together, these results suggest that Cux-1 may function in the context of the Notch signaling pathway in multiple tissues during mammalian embryogenesis.

Animals↗
PubMed1995

TLE expression correlates with mouse embryonic segmentation, neurogenesis, and epithelial determination.

The TLE proteins are the mammalian homologues of Groucho, a member of the Drosophila Notch signaling pathway. Notch signaling controls the differentiation of a variety of tissues in invertebrates and vertebrates. We are investigating the role of the TLE genes during mammalian development. We show that TLE 1 and TLE 3 are expressed during a number of cell-determination events, including embryonic segmentation, central and peripheral neurogenesis, and epithelial differentiation. This expression pattern is in agreement with the involvement of Groucho in similar fate choices in Drosophila and suggests that Groucho and TLE proteins perform similar developmental roles. Our results also show that TLE genes are co-expressed during a variety of cell-fate choices with several vertebrate homologues of genes implicated in the Drosophila Notch cascade, suggesting a role for the TLE proteins in mammalian Notch signaling.

Animals↗
PubMed2005

Notch1 is essential for postnatal hair follicle development and homeostasis.

Notch genes encode evolutionarily conserved large, single transmembrane receptors, which regulate many cell fate decisions and differentiation processes during fetal and postnatal life. Multiple Notch receptors and ligands are expressed in both developing and adult epidermis and hair follicles. Proliferation and differentiation of these two ectodermal-derived structures have been proposed to be controlled in part by the Notch pathway. Whether Notch signaling is involved in postnatal hair homeostasis is currently unknown. Here, we investigate and compare the role of the Notch1 receptor during embryonic hair follicle development and postnatal hair homeostasis using Cre-loxP based tissue specific and inducible loss-of-function approaches. During embryonic development, tissue-specific ablation of Notch1 does not perturb formation and patterning of hair follicle placodes. However, Notch1 deficient hair follicles invaginate prematurely into the dermis. Embryonic as well as postnatal inactivation of Notch1 shortly after birth or in adult mice results in almost complete hair loss followed by cyst formation. The first hair cycle of Notch1 deficient mice is characterized by shortened anagen and a premature entry into catagen. These data show that Notch1 is essential for late stages of hair follicle development during embryogenesis as well as for post-natal hair follicle development and hair homeostasis.

Animals↗
PubMed1998

Distinct expression patterns of notch family receptors and ligands during development of the mammalian inner ear.

The cochlea and vestibular structures of the inner ear labyrinth develop from the otic capsule via step-wise regional and cell fate specification. Each inner ear structure contains a sensory epithelium, composed of hair cells, the mechanosensory transducers, and supporting cells. We examined the spatio-temporal expression of genes in the Notch signaling pathway, Notch receptors (Notch1-4) and two ligands, Jagged1 and Delta1, in the developing mammalian inner ear. Our results show that Notch1 and Jagged1 are first expressed in the otic vesicle, likely involved in differentiation of the VIIIth nerve ganglion neurons, and subsequently within the inner ear sensory epithelia, temporally coincident with initial hair cell differentiation. Notch1 expression is specific to hair cells and Jagged1 to supporting cells. Their expression persists into adult. Notch2, Notch3, Notch4, and Delta1 are excluded from the inner ear epithelia. These data support the hypothesis that Notch signaling is involved in hair cell differentiation during inner ear morphogenesis.

Animals↗
PubMed2006

Neuralized-2 regulates a Notch ligand in cooperation with Mind bomb-1.

Mutations in Drosophila neuralized (Dneur) result in a variety of developmental defects that closely resemble those of Notch mutants and other Notch pathway mutants. However, mice with disrupted neur1 do not show any aberrant cell fate specifications in neurogenesis and somitogenesis. Thus, we speculated that other vertebrate neur homolog(s) might compensate for loss of the neur gene. Here, we report the paralog of mouse Neur1, named Neuralized-2 (Neur2), which is a ubiquitin-protein isopeptide ligase (E3) that interacts with and ubiquitinates Delta. Both murine Neur1 and Neur2 have similar degrees of homology to DNeur, and neur2 is expressed in patterns similar to those of neur1 in embryos, suggesting potential functional redundancy. Interestingly, two distinct classes of E3 ligases, Mind bomb-1 (Mib1) and Neur2, have cooperative but distinct roles in Delta endocytosis to Hrs-positive vesicles, i.e. Mib1 functions in the initial step of Delta endocytosis, and Neur2 is required for targeting endocytosed Delta to Hrs-positive vesicles. Thus, our study provides a new insight into how distinct E3 ligases work together in the endocytic pathways for Notch signaling.

Amino Acid Sequence↗
PubMed2004

Minireview: Development and differentiation of gut endocrine cells.

For over 30 yr, it has been known that enteroendocrine cells derive from common precursor cells in the intestinal crypts. Until recently, relatively little was understood about the events that result in commitment to endocrine differentiation or the segregation of over 10 different hormone-expressing cell types in the gastrointestinal tract. The earliest cell fate decisions appear to be regulated by the Notch signaling pathway. Notch is inactive in endocrine precursor cells, allowing for expression of the proendocrine basic helix-loop-helix proteins Math1 and neurogenin3. Differentiating precursor cells activate Notch in neighboring cells to switch off expression of proendocrine factors and inhibit endocrine differentiation. Math1 is the first factor involved in endocrine specification, committing cells to become one of three secretory lineages-goblet, Paneth, and enteroendocrine. Neurogenin3 appears to be a downstream target that is essential for endocrine cell differentiation. Events that control the segregation of each mature lineage from progenitor cells have not been characterized in detail. The transcription factors Pax4, Pax6, BETA2/NeuroD, and pancreatic-duodenal homeobox 1 have all been implicated in enteroendocrine differentiation. BETA2/NeuroD appears to coordinate secretin gene expression in S-type enteroendocrine cells with cell cycle arrest as cells terminally differentiate. Powerful genetic approaches have established the murine intestine as the most important model for studying enteroendocrine differentiation. Enteroendocrine cells in the mouse are remarkably similar to those in humans, making it likely that insights learned from the mouse may contribute to both our understanding and treatment of a variety of human disorders.

Animals↗
PubMed2006

Inhibition of endothelial cell proliferation by Notch1 signaling is mediated by repressing MAPK and PI3K/Akt pathways and requires MAML1.

The requirement for Notch signaling in vasculogenesis and angiogenesis is well documented. In a previous study, we showed that activation of the Notch pathway in endothelial cells induces differentiation-associated growth arrest; however, the underlying mechanism remains to be elucidated. Here, we show that activation of the Notch pathway by either stimulation of cell surface Notch receptors with crosslinked soluble delta-like 4 (sDll4)/Jagged1 (sJag1) or constitutive expression of the Notch1 intracellular domain (N(IC)) suppresses endothelial cell proliferation. This suppression is mediated by the mitogen-activated protein kinase (MAPK) and phosphatidylinositol 3-kinase (PI3K)/Akt pathways. Following Notch1 activation, both pathways were suppressed in endothelial cells, and alterations in MAPK or PI3K/Akt pathway activity reversed Notch1-induced growth inhibition. Furthermore, we found the effect of Notch1 on endothelial cells to require Mastermind-like (MAML). Overexpression of a dominant-negative mutant of MAML1 antagonized the effects of activated Notch1 on the MAPK and PI3K/Akt pathways. Ectopic expression of Hairy/Enhancer of Split 1 (HES1) consistently reproduced the inhibitory effect of N(IC) on endothelial cell proliferation. Together, our data demonstrate that the Notch/MAML-HES signaling cascade can regulate both MAPK and PI3K/Akt pathways, which suggests a molecular mechanism for the inhibitory effect of Notch signaling on endothelial cell proliferation.

Cell Proliferation↗
PubMed2006

NOTCH2 mutations cause Alagille syndrome, a heterogeneous disorder of the notch signaling pathway.

Alagille syndrome (AGS) is caused by mutations in the gene for the Notch signaling pathway ligand Jagged1 (JAG1), which are found in 94% of patients. To identify the cause of disease in patients without JAG1 mutations, we screened 11 JAG1 mutation-negative probands with AGS for alterations in the gene for the Notch2 receptor (NOTCH2). We found NOTCH2 mutations segregating in two families and identified five affected individuals. Renal manifestations, a minor feature in AGS, were present in all the affected individuals. This demonstrates that AGS is a heterogeneous disorder and implicates NOTCH2 mutations in human disease.

Alagille Syndrome↗
PubMed2005

The REF-1 family of bHLH transcription factors pattern C. elegans embryos through Notch-dependent and Notch-independent pathways.

Much of the patterning of early C. elegans embryos involves a series of Notch interactions that occur in rapid succession and have distinct outcomes; however, none of the targets for these interactions have been identified. We show that the REF-1 family of bHLH transcription factors is a major target of Notch signaling in all these interactions and that most examples of Notch-mediated transcriptional repression can be attributed to REF-1 activities. The REF-1 family is expressed and has similar functions in both Notch-dependent and Notch-independent pathways, and this dual mode of deployment is used repeatedly to pattern the embryo. REF-1 proteins are unusual in that they contain two different bHLH domains and lack the distinguishing characteristics of Hairy/Enhancer of Split (HES) bHLH proteins that are Notch targets in other systems. Our results show that the highly divergent REF-1 proteins are nonetheless HES-like bHLH effectors of Notch signaling.

Age Factors↗