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PubMed2006

Expression of Notch signaling pathway genes in mouse embryos lacking beta4galactosyltransferase-1.

A requirement for beta4galactosyltransferase-1 (beta4GalT-1) activity in the modulation of Notch signaling by the glycosyltransferase Fringe was previously identified in a mammalian co-culture assay. Notch signaling is necessary for the formation of somites in mammals. We therefore investigated the expression of eleven Notch pathway and somitogenic genes in E9.5 mouse embryos lacking beta4GalT-1. Four of these genes were altered in expression pattern or expression level. The Notch target genes Hes5 and Mesp2 were affected to some degree in all mutant embryos. The Notch ligand genes Dll1 and Dll3 were reduced or altered in expression in a significant proportion of mutants. While there were no differences in the number or morphology of somites in E9.5 B4galt1 null embryos, the number of lumbar vertebrae in mutant embryos differed from control littermates (P < or = 0.01). The subtlety of the in vivo phenotype may be due to redundancy since several B4galt genes related to B4galt1 are expressed during embryogenesis.

Animals↗
PubMed2006

Structures of CSL, Notch and Mastermind proteins: piecing together an active transcription complex.

Notch signaling mediates communication between cells, and is essential for proper cell fate decisions in the developing embryo and the adult organism. Signaling initiates proteolytic release of the receptor Notch from the membrane, whereupon the intracellular portion of Notch (NotchIC) localizes to the nucleus and engages the DNA-binding transcription factor CSL. CSL is required for both repression and activation of Notch target genes, and is the focal point of a transcriptional switch, mediating interactions with transcriptional coregulators. Activation of transcription requires corepressor displacement from CSL by NotchIC and the recruitment of the transcriptional coactivator Mastermind to the complex. Several recently determined and exciting structures of CSL, NotchIC, and an active transcription complex composed of CSL, NotchIC and Mastermind have revealed new insights into transcriptional regulation in the Notch pathway.

Animals↗
PubMed2004

Notch in mammary gland development and breast cancer.

Notch signaling has been implicated in many processes including cell fate determination and oncogenesis. In mice, the Notch1 and Notch4 genes are both targets for insertion and rearrangement by the mouse mammary tumor virus and these mutations promote epithelial mammary tumorigenesis. Moreover, expression of a constitutively active form of Notch4 in mammary epithelial cells inhibits epithelial differentiation and leads to tumor formation in this organ. These data implicate the Notch pathway in breast tumorigenesis and provide the foundation for future experiments that will aid in our understanding of the role of Notch in human breast cancer development. Here, we review studies of mammary tumorigenesis induced by Notch in mouse and in vitro culture models providing evidence that Notch activation is a causal factor in human breast cancer.

Breast Neoplasms↗
PubMed2004

Notch in lung development and lung cancer.

Although data regarding the role of the Notch pathway in human lung cancer are still limited, fetal lung developmental studies suggest that Notch signaling plays a critical role in regulating airway epithelial development. The moderate hypotrophic phenotype of lungs from animals bearing a Hes1 mutation, and the expression of Notch components in the distal lung bud during branching morphogenesis, together suggest that Notch may play a role in normal lung growth, especially in Clara cell precursors. Non-small cell lung cancers, including adenocarcinoma, appear to actively utilize this conserved developmental pathway. Pharmacologic inhibition of the Notch pathway is a potential experimental approach to lung cancer treatment.

Animals↗
PubMed2004

Viral interactions with the Notch pathway.

The Notch signaling pathway influences cell fate decisions, proliferation versus differentiation and cell survival. Viruses both utilize and manipulate the differentiation state of infected cells, promote or block cell cycling and employ a variety of mechanisms to evade innate cellular anti-viral responses and promote cell survival. In light of these commonalities, it is perhaps not surprising that several viruses have tapped into the Notch pathway to advance their own life cycles. This first became apparent from studies showing targeting of Epstein-Barr virus proteins to the nuclear effector of Notch signaling CSL (CBF1/RBPJk). More recently the Kaposi's sarcoma-associated herpesvirus RTA protein has been found to bind CSL. Notch pathway interactions have also been described for adenovirus SV40 and human papilloma virus. This review focuses on the herpesvirus protein interactions with the Notch pathway and the insights that these interactions have provided.

Animals↗
PubMed2005

Mouse hesr1 and hesr2 genes are redundantly required to mediate Notch signaling in the developing cardiovascular system.

Notch signaling is required for multiple aspects of cardiovascular development, including arterial-venous differentiation, septation and cushion formation. Despite recognition of the importance of the Notch pathway in normal cardiovascular development, the proximate downstream effectors are not yet known. Likely candidate effectors are members of the hairy and enhancer of split related (hesr) family of bHLH transcription factors. However, mutational analysis of individual hesr genes has so far failed to elucidate their role in all Notch-mediated cardiovascular signaling events. An example of this is evident for mutants of gridlock, the zebrafish counterpart of mouse hesr2, which have vascular defects, whereas mouse hesr2 mutants have only cardiac defects. One possible explanation for these differences could be functional redundancy between hesr family members. Here, we report that mice lacking the hesr1 gene are viable and fertile, whereas knockout mouse of both hesr1 and hesr2 is embryonic lethal at 11.5 days postcoitum (dpc) and recapitulates most of the known cardiovascular phenotypes of disrupted Notch pathway mutants including defects in arterial-venous specification, septation and cushion formation. Taken together, our results demonstrate a requirement for hesr1 and hesr2 in mediating Notch signaling in the developing cardiac and vascular systems.

Animals↗
PubMed2005

Notch-Delta signaling is required for spatial patterning and Müller glia differentiation in the zebrafish retina.

Notch-Delta signaling has been implicated in several alternative modes of function in the vertebrate retina. To further investigate these functions, we examined retinas from zebrafish embryos in which bidirectional Notch-Delta signaling was inactivated either by the mind bomb (mib) mutation, which disrupts E3 ubiquitin ligase activity, or by treatment with gamma-secretase inhibitors, which prevent intramembrane proteolysis of Notch and Delta. We found that inactivating Notch-Delta signaling did not prevent differentiation of retinal neurons, but it did disrupt spatial patterning in both the apical-basal and planar dimensions of the retinal epithelium. Retinal neurons differentiated, but their laminar arrangement was disrupted. Photoreceptor differentiation was initiated normally, but its progression was slowed. Although confined to the apical retinal surface as in normal retinas, the planar organization of cone photoreceptors was disrupted: cones of the same spectral subtype were clumped rather than regularly spaced. In contrast to neurons, Müller glia failed to differentiate suggesting an instructive role for Notch-Delta signaling in gliogenesis.

Animals↗
PubMed2005

Serrate-Notch signaling defines the scope of the initial denticle field by modulating EGFR activation.

The Drosophila embryonic epidermis has been a key model for understanding the establishment of cell type diversity across a cellular field. During segmental patterning, distinct signaling territories are established that employ either the Hedgehog, Spitz, Serrate or Wingless ligands. How these pathways control segmental pattern is not completely clear. One major decision occurs as cells are allocated to differentiate either smooth cuticle or denticle type cuticle. This allocation is based on competition between Wingless signaling and Spitz, which activates the Epidermal Growth Factor Receptor (EGFR). Here we show that a main role for Serrate-Notch signaling is to adjust the Spitz signaling domain. Serrate accomplishes this task by activating Notch in a discrete domain, the main purpose of which is to broaden the spatially regulated expression of Rhomboid. This adjusts the breadth of the source for Spitz, since Rhomboid is necessary for the production of active Spitz. We also show that the Serrate antagonist, fringe, must temper Notch activity to insure that the activation of the EGFR is not too robust. Together, Serrate and Fringe modulate Notch activation to generate the proper level of EGFR activation. If Serrate-Notch signaling is absent, the denticle field narrows while the smooth cell field expands, as judged by the expression of the denticle field determinant Ovo/Shaven baby. This establishes one important role for the Serrate signaling territory, which is to define the extent of denticle field specification.

Animals↗
PubMed2005

tortuga refines Notch pathway gene expression in the zebrafish presomitic mesoderm at the post-transcriptional level.

We have identified the zebrafish tortuga (tor) gene by an ENU-induced mutation that disrupts the presomitic mesoderm (PSM) expression of Notch pathway genes. In tor mutants, Notch pathway gene expression persists in regions of the PSM where expression is normally off in wild type embryos. The expression of hairy/Enhancer of split-related 1 (her1) is affected first, followed by the delta genes deltaC and deltaD, and finally, by another hairy/Enhancer of split-related gene, her7. In situ hybridization with intron-specific probes for her1 and deltaC indicates that transcriptional bursts of expression are normal in tor mutants, suggesting that tor normally functions to refine her1 and deltaC message levels downstream of transcription. Despite the striking defects in Notch pathway gene expression, somite boundaries form normally in tor mutant embryos, although somitic mesoderm defects are apparent later, when cells mature to form muscle fibers. Thus, while the function of Notch pathway genes is required for proper somite formation, the tor mutant phenotype suggests that precise oscillations of Notch pathway transcripts are not essential for establishing segmental pattern in the presomitic mesoderm.

Animals↗
PubMed2006

Notch signaling regulates midline cell specification and proliferation in zebrafish.

Notochord and floor plate cells are sources of molecules that pattern tissues near the midline, including the spinal cord. Hypochord cells are also found at the midline of anamniote embryos and are important for aorta development. Delta-Notch signaling regulates midline patterning in the dorsal organizer by inhibiting notochord formation and promoting hypochord and possibly floor plate development, but the precise mechanisms by which this regulation occurs are unknown. We demonstrate here that floor plate and hypochord cells arise from distinct regions of the zebrafish shield. Blocking Notch signaling during gastrulation entirely prevented hypochord specification but only reduced the number of floor plate cells that developed compared to control embryos. In contrast, elevation of Notch signaling at the beginning of gastrulation caused expansion of hypochord at the expense of notochord, but floor plate was not affected. A cell proliferation assay revealed that Notch signaling maintains dividing floor plate progenitors. Together, our results indicate that Notch signaling regulates allocation of appropriate numbers of different midline cells by different mechanisms.

Animals↗
PubMed2006

The Notch signaling pathway in the cnidarian Hydra.

Many of the major pathways that govern early development in higher animals have been identified in cnidarians, including the Wnt, TGFbeta and tyrosine kinase signaling pathways. We show here that Notch signaling is also conserved in these early metazoans. We describe the Hydra Notch receptor (HvNotch) and provide evidence for the conservation of the Notch signaling mode via regulated intramembrane proteolysis. We observed that nuclear translocation of the Notch intracellular domain (NID) was inhibited by the synthetic gamma-secretase inhibitor DAPT. Moreover, DAPT treatment of hydra polyps caused distinct differentiation defects in their interstitial stem cell lineage. Nerve cell differentiation proceeded normally but post-mitotic nematocyte differentiation was dramatically reduced. Early female germ cell differentiation was inhibited before exit from mitosis. From these results we conclude that gamma-secretase activity and presumably Notch signaling are required to control differentiation events in the interstitial cell lineage of Hydra.

Active Transport, Cell Nucleus↗
PubMed2004

Altered Notch signaling resulting from expression of a WAMTP1-MAML2 gene fusion in mucoepidermoid carcinomas and benign Warthin's tumors.

Chromosome translocations in neoplasia commonly result in fusion genes that may encode either novel fusion proteins or normal, but ectopically expressed proteins. Here we report the cloning of a novel fusion gene in a common type of salivary and bronchial gland tumor, mucoepidermoid carcinomas (MEC), as well as in benign Warthin's tumors (WATs). The fusion, which results from a t(11;19)(q21-22;p13) translocation, creates a chimeric gene in which exon 1 of a novel gene of unknown function, designated WAMTP1, is linked to exons 2-5 of the recently identified Mastermind-like Notch coactivator MAML2. In the fusion protein, the N-terminal basic domain of MAML2, which is required for binding to intracellular Notch (Notch ICD), is replaced by an unrelated N-terminal sequence from WAMTP1. Mutation analysis of the N-terminus of WAMTP1-MAML2 identified two regions of importance for nuclear localization (amino acids 11-20) and for colocalization with MAML2 and Notch1 ICD in nuclear granules (amino acids 21-42). Analyses of the Notch target genes HES5 and MASH1 in MEC tumors with and without the WAMTP1-MAML2 fusion revealed upregulation of HES5 and downregulation of MASH1 in fusion positive MECs compared to normal salivary gland tissue and MECs lacking the fusion. These findings suggest that altered Notch signaling plays an important role in the genesis of benign and malignant neoplasms of salivary and bronchial gland origin.

Adenolymphoma↗
PubMed2003

The Drosophila IgC2 domain protein Friend-of-Echinoid, a paralogue of Echinoid, limits the number of sensory organ precursors in the wing disc and interacts with the Notch signaling pathway.

The Notch signaling pathway is critical in cell fate specification throughout development. In the developing wing disc, single sensory organ precursors (SOPs) are selected from proneural clusters via a process of lateral inhibition mediated by the Notch signaling pathway. The epidermal growth factor receptor (EGFR) pathway has also been implicated in SOP formation. Here, we describe the Drosophila melanogaster gene friend of echinoid (fred), a paralogue of echinoid (ed), a gene recently identified as a negative regulator of the EGFR pathway. fred function was examined in transgenic flies by using inducible RNA interference (RNAi). Suppression of fred in developing wing discs results in specification of ectopic SOPs, additional microchaeta, and cell death. In eye-antennal discs, fred suppression causes a rough eye phenotype. These phenotypes are suppressed by overexpression of Notch, Suppressor of Hairless [Su(H)], and Enhancer of split m7. In contrast, overexpression of Hairless, a negative regulator of the Notch pathway, and decreased Su(H) activity enhance these phenotypes. Thus, fred acts in close concert with the Notch signaling pathway. Dosage-sensitive genetic interaction also suggests a close relationship between fred and ed.

Amino Acid Sequence↗
PubMed1996

An activated form of Notch influences the choice between CD4 and CD8 T cell lineages.

Notch is a transmembrane receptor that controls cell fate decisions in Drosophila and whose role in mammalian cell fate decisions is beginning to be explored. We are investigating the role of Notch in a well-studied mammalian cell fate decision: the choice between the CD8 and CD4 T cell lineages. Here we report that expression of an activated form of Notch1 in developing T cells of the mouse leads to both an increase in CD8 lineage T cells and a decrease in CD4 lineage T cells. Expression of activated Notch permits the development of mature CD8 lineage thymocytes even in the absence of class I major histocompatability complex (MHC) proteins, ligands that are normally required for the development of these cells. However, activated Notch is not sufficient to promote CD8 cell development when both class I and class II MHC are absent. These results implicate Notch as a participant in the CD4 versus CD8 lineage decision.

Animals↗
PubMed2002

Expression of Notch ligands, Jagged1, 2 and Delta1 in antigen presenting cells in mice.

Notch1 is indispensable for T cell development. It is anticipated that Notch1 and other Notch receptors expressed on the surface of thymic T cell precursors are activated by ligands present on environmental cells, including antigen presenting cells (APCs), and involved in positive and negative selections. Notch receptors on peripheral T cells may also be activated by ligands on APCs. Here, we examined the expression pattern of three Notch ligands, Jagged1, 2 and Delta1 in APCs by an immunofluorescence cell staining method and a reverse transcriptase-polymerase chain reaction (RT-PCR) method. Peritoneal macrophages were strongly positive for Jagged1 staining. In contrast, macrophages separated from spleen and dendritic cells (DCs) separated from spleen and thymus showed positive staining for all the three ligands at a similar intensity. An analysis by RT-PCR revealed that peritoneal and splenic macrophages and splenic and thymic DCs, show a distinct pattern in Notch ligand expression. These findings may represent that expression of various Notch ligands in APCs has a physiological relevance in each organ.

Animals↗
PubMed2001

Radical fringe negatively modulates Notch signaling in postmitotic neurons of the rat brain.

Fringe was originally identified as a novel secreted signaling protein with a key role in wing formation of Drosophila. Three vertebrate fringe homologues, Radical, Lunatic and Manic fringe, were also identified, and have been shown to play major roles in neurogenesis during development. However, the expression and roles of vertebrate fringe homologues in the adult brain remain to be elucidated. We isolated the cDNA encoding rat Radical fringe (334 amino acids) from rat embryos, and found its mRNA to be most abundantly expressed in the adult rat brain by Northern blotting analysis. The localization of Radical fringe mRNA in the adult rat brain was also examined by in situ hybridization. The mRNA was abundantly expressed in most neurons, but not glial cells, throughout the brain. Notch signaling was shown to negatively modulate the stability of neurites and connections in postmitotic primary neurons. Furthermore, genetic evidence indicated that fringe modulated the Notch signaling pathway. Therefore, we examined the effects of Radical fringe on the Notch signaling pathway in primary rat neurons of the cerebral cortex using recombinant rat Radical fringe protein. Radical fringe protein significantly inhibited expression of the Notch effector Hes1 mRNA in primary neurons. These results indicated that Radical fringe functions by inhibiting Notch signaling in postmitotic neurons of the brain.

Amino Acid Sequence↗
PubMed2001

Murine homologs of deltex define a novel gene family involved in vertebrate Notch signaling and neurogenesis.

Notch signaling plays an important role in cell-fate specification in multicellular organisms by regulating cell-cell communication. The Drosophila deltex gene encodes a modulator of the Notch pathway that has been shown to interact physically with the Ankyrin repeats of Notch. We isolated four distinct cDNAs corresponding to mouse homologs of deltex - mouse Deltex1 (MDTX1), mouse Deltex2 (MDTX2), mouse Deltex2DeltaE (MDTX2DeltaE), and mouse Deltex3 (MDTX3). Deduced amino acid sequences of these four cDNAs showed a high degree of similarity to Drosophila Deltex and its human homolog, DTX1 throughout their lengths, even though they possess distinct structural features. MDTX proteins formed homotypic and heterotypic multimers. We found that these genes were expressed in the central, peripheral nervous system and in the thymus, overlapping with those of mouse Notch1. In mammalian tissue culture cells, overexpression of any of the four mouse deltex homologs suppressed the transcriptional activity of E47, a basic helix-loop-helix (bHLH) protein, in a manner similar to suppression by an activated form of human Notch1 or human DTX1. In addition, overexpression of MDTX2 and MDTX2DeltaE in C2C12 cells under differentiation-inducing conditions suppressed the expression of myogenin, one of the myogenic transcriptional factors; this was also similar to a previously reported activity of constitutively activated Notch. Furthermore, misexpression of any of the MDTX genes in Xenopus embryos resulted in an expansion of the region expressing the neural cell adhesion molecule (N-CAM) gene, a marker for the neuroepithelium. Collectively, our results suggest that these mouse deltex homologs are involved in vertebrate Notch signaling and regulation of neurogenesis.

Amino Acid Sequence↗
PubMed1998

Characterization of Drosophila Presenilin and its colocalization with Notch during development.

Mutant Presenilin proteins cause early-onset familial Alzheimer's disease in humans and Caenorhabditis elegans Presenilins may facilitate Notch receptor signaling. We have isolated a Drosophila Presenilin homologue and determined the spatial and temporal distribution of the encoded protein as well as its localization relative to the fly Notch protein. In contrast to previous mRNA in situ studies, we find that Presenilin is widely expressed throughout oogenesis, embryogenesis, and imaginal development, and generally accumulates at comparable levels in neuronal and nonneuronal tissues. Double immunolabeling with Notch antibodies revealed that Presenilin and Notch are coexpressed in many tissues throughout Drosophila development and display partially overlapping subcellular localizations, supporting a possible functional link between Presenilin and Notch.

Amino Acid Sequence↗