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PubMed2005

Notch signaling modulates the nuclear localization of carboxy-terminal-phosphorylated smad2 and controls the competence of ectodermal cells for activin A.

Loss of mesodermal competence (LMC) during Xenopus development is a well known but little understood phenomenon that prospective ectodermal cells (animal caps) lose their competence for inductive signals, such as activin A, to induce mesodermal genes and tissues after the start of gastrulation. Notch signaling can delay the onset of LMC for activin A in animal caps [Coffman, C.R., Skoglund, P., Harris, W.A., Kintner, C.R., 1993. Expression of an extracellular deletion of Xotch diverts cell fate in Xenopus embryos. Cell 73, 659-671], although the mechanism by which this modulation occurs remains unknown. Here, we show that Notch signaling also delays the onset of LMC in whole embryos, as it did in animal caps. To better understand this effect and the mechanism of LMC itself, we investigated at which step of activin signal transduction pathway the Notch signaling act to affect the timing of the LMC. In our system, ALK4 (activin type I receptor) maintained the ability to phosphorylate the C-terminal region of smad2 upon activin A stimulus after the onset of LMC in both control- and Notch-activated animal caps. However, C-terminal-phosphorylated smad2 could bind to smad4 and accumulate in the nucleus only in Notch-activated animal caps. We conclude that LMC was induced because C-terminal-phosphorylated smad2 lost its ability to bind to smad4, and consequently could not accumulate in the nucleus. Notch signal activation restored the ability of C-terminal-phosphorylated smad2 to bind to smad4, resulting in a delay in the onset of LMC.

Activin Receptors↗
PubMed2005

Ligand-binding and signaling properties of the Ax[M1] form of Notch.

The Abruptex class of Notch alleles has attracted interest because they exhibit some properties that are best explained in terms of increased activity and others that are best explained in terms of reduced activity in vivo. Here, we report a comparison of the properties of Abruptex[M1] and wild-type Notch as ligand binding receptors. Abruptex[M1] showed less activity than wild-type Notch in its ability to bind Delta and Serrate and was expressed at reduced levels on the cell surface. When differences in expression level were taken into account, Abruptex[M1] was comparable to Notch in its sensitivity to ligand-induced activation of reporter gene expression. Abruptex[M1] was also comparable to Notch in its requirement for modification by Fringe and in being sensitive to cis-dowregulation by co-expressed ligands. By the available criteria Abruptex[M1] exhibits less activity than Notch. To explain the ectopic activity of Abruptex[M1] in vivo we suggest that it may be necessary to invoke an altered response to an as yet unidentified ligand or cofactor.

Alleles↗
PubMed2006

XMam1, Xenopus Mastermind1, induces neural gene expression in a Notch-independent manner.

Mastermind, which is a Notch signal component, is a nuclear protein and is thought to contribute to the transactivation of target genes. Previously we showed that XMam1, Xenopus Mastermind1, was essential in the transactivation of a Notch target gene, XESR-1, and was involved in primary neurogenesis. To examine the function of XMam1 during Xenopus early development in detail, XMam1-overexpressed embryos were analyzed. Overexpression of XMam1 ectopically caused the formation of a cell mass with pigmentation on the surface of embryos and expressed nrp-1. The nrp-1-positive cell mass was produced by XMam1 without expression of the Notch target gene, XESR-1, and not by the activation form of Notch, NICD. The ectopic expression of nrp-1 was not inhibited by co-injection of XMam1 with a molecule known to inhibit Notch signaling. The nrp-1 expression was also recognized in the animal cap injected with XMam1DeltaN, which lacks the basic domain necessary for interacting with NICD and Su(H). These results show that XMam1 has the ability to induce the cell fate into the neurogenic lineage in a Notch-independent manner.

Animals↗
PubMed2004

Notch activation induces apoptosis in neural progenitor cells through a p53-dependent pathway.

Notch signaling is involved in a variety of cell-fate decisions during development. Here we investigate the role of Notch signaling in apoptotic cell death of neural progenitors through the generation and analysis of cell type-specific conditional transgenic and knockout mice. We show that conditional expression of a constitutively active form of Notch1 in early neural progenitor cells, but not postmitotic neurons, selectively induces extensive apoptosis, resulting in a markedly reduced progenitor population. Conversely, attenuation of Notch signaling in Notch1 conditional knockout or Presenilin-1-/- mice results in reduced apoptosis of early neural progenitor cells. Furthermore, Notch activation in neural progenitor cells leads to elevated levels of nuclear p53 and transcriptional upregulation of the target genes Bax and Noxa, and the promotion of apoptotic cell death by Notch activation is completely suppressed by p53 deficiency. Together, these complementary gain-of-function and loss-of-function studies reveal a previously unappreciated role of Notch signaling in the regulation of apoptotic cell death during early mammalian neural development.

Animals↗
PubMed2005

Suppressor of Hairless and Presenilin phenotypes imply involvement of canonical Notch-signalling in segmentation of the spider Cupiennius salei.

Arthropods, vertebrates, and annelids all have a segmented body. Our recent discovery of involvement of Notch-signalling in spider segmentation revived the discussion on the origin of segmented body plans and suggests the sharing of a common genetic program in a common ancestor. Here, we analysed the spider homologues of the Suppressor of Hairless and Presenilin genes, which encode components of the canonical Notch-pathway, to further explore the role of Notch-signalling in spider segmentation. RNAi silencing of two spider Suppressor of Hairless homologues and the spider Presenilin homologue causes severe segmentation phenotypes. The most prominent defect is the consistent breakdown of segmentation after the formation of three (Suppressor of Hairless) or five (Presenilin) opisthosomal segments. These phenotypes indicate that Notch-signalling during spider segmentation likely involves the canonical pathway via Presenilin and Suppressor of Hairless. Furthermore, it implies that Notch-signalling influences both the formation and patterning of the spider segments: it is required for the specification of the posterior segments and for proper specification of the segment boundaries. We argue that alternative, partly redundant, pathways might act in the formation of the anterior segments that are not active in the posterior segments. This suggests that at least some differences exist in the specification of anterior and posterior segments of the spider, a finding that may be valid for most short germ arthropods. Our data provide additional evidence for the similarities of Notch-signalling in spider segmentation and vertebrate somitogenesis and strengthen our previous notion that the formation of the segments in arthropods and vertebrates might have shared a genetic program in a common ancestor.

Amino Acid Sequence↗
PubMed2005

Distinct roles of EGF repeats for the Notch signaling system.

Notch is a single-pass transmembrane receptor that mediates cell fate choice in various species and developmental contexts. The Notch signal is transduced by its intracellular domain, which acts as a transcriptional activator, and is released from the plasma membrane by proteolytic cleavages. This process is initiated by intercellular association of the epidermal growth factor (EGF) repeats between Notch and the DSL (Delta, Serrate, Lag-2) ligands but the detailed mechanism is yet to be clarified. Here we demonstrate that Notch1 can form homodimers, which is achieved by its EGF motifs. The Notch1 dimer formation increased in response to ligand presentation and HES1 promoter was stimulated, implying that receptor homodimerization is an important initial step in Notch signal transduction. EGF motifs also serve as a protection against proteases, including TNF-alpha converting enzyme, which prevents Notch1 from ligand-independent activation. Multiple functions of the Notch EGF motifs, such as the prevention of constitutive activation, reciprocal interaction with the ligands and lateral interaction for homodimerization, appear to constitute crucial elements of the Notch signaling system.

Amino Acid Motifs↗
PubMed2006

Hypoxia-mediated activation of Dll4-Notch-Hey2 signaling in endothelial progenitor cells and adoption of arterial cell fate.

Adequate response to low oxygen levels (hypoxia) by hypoxia inducible factor (HIF) is essential for normal development and physiology, but this pathway may also contribute to pathological processes like tumor angiogenesis. Here we show that hypoxia is an inducer of Notch signaling. Hypoxic conditions lead to induction of the Notch ligand Dll4 and the Notch target genes Hey1 and Hey2 in various cell lines. Promoter analysis revealed that Hey1, Hey2 and Dll4 are induced by HIF-1alpha and Notch activation. Hypoxia-induced Notch signaling may also determine endothelial identity. Endothelial progenitor cells (EPCs) contain high amounts of COUP-TFII, a regulator of vein identity, while levels of the arterial regulators Dll4 and Hey2 are low. Hypoxia-mediated upregulation of Dll4 and Hey2 leads to repression of COUP-TFII in eEPCs. Finally, we show that Hey factors are capable of repressing HIF-1alpha-induced gene expression, suggesting a negative feedback loop to prevent excessive hypoxic gene induction. Thus, reduced oxygen levels lead to activation of the Dll4-Notch-Hey2 signaling cascade and subsequent repression of COUP-TFII in endothelial progenitor cells. We propose that this is an important step in the developmental regulation of arterial cell fate decision.

Adaptor Proteins, Signal Transducing↗
PubMed2003

The tumour suppressor gene l(2)giant discs is required to restrict the activity of Notch to the dorsoventral boundary during Drosophila wing development.

During the development of the Drosophila wing, the activity of the Notch signalling pathway is required to establish and maintain the organizing activity at the dorsoventral boundary (D/V boundary). At early stages, the activity of the pathway is restricted to a small stripe straddling the D/V boundary, and the establishment of this activity domain requires the secreted molecule fringe (fng). The activity domain will be established symmetrically at each side of the boundary of Fng-expressing and non-expressing cells. Here, I present evidence that the Drosophila tumour-suppressor gene lethal (2) gaint discs (lgd) is required to restrict the activity of Notch to the D/V boundary. In the absence of lgd function, the activity of Notch expands from its initial domain at the D/V boundary. This expansion requires the presence of at least one of the Notch ligands, which can activate Notch more efficiently in the mutants. The results further suggest that Lgd appears to act as a general repressor of Notch activity, because it also affects vein, eye, and bristle development.

Animals↗
PubMed1998

A role for Abl in Notch signaling.

Abl is an axonal tyrosine kinase that has yet to be clearly linked to a receptor; Notch is a receptor for which the signaling pathway remains incompletely understood. We show here that Notch and abl mutations interact synergistically to produce synthetic lethality and defects in axon extension. Surprisingly, we cannot account for these axonal aberrations on the basis of changes in cell identity. We show, moreover, that Notch is present in the growth cones of extending axons, and that the Abl accessory protein Disabled binds to a signaling domain of Notch in vitro. We therefore speculate that Disabled and Abl may play a role in Notch signaling in Drosophila axons, perhaps by binding to the Notch intracellular domain.

Animals↗
PubMed2002

Wing vein formation in Drosophila melanogaster: hairless is involved in the cross-talk between Notch and EGF signaling pathways.

Wing vein development in Drosophila is controlled by different morphogenetic pathways, including Notch. Hairless (H) antagonizes Notch target gene activation by binding to the Notch signal transducer Suppressor of Hairless [Su(H)]. Accordingly, overexpression of H phenocopies reduction of Notch activity. Deletion of the Su(H)-binding domain in H-C2 results in loss of H activity. However, overexpression of H-C2 induces formation of ectopic veins. In a screen for genetic modifiers of this phenotype, we have identified several genes involved in Notch and epidermal growth factor (EGF) signaling. Most notably veinlet, an activator of EGF signaling, acts downstream of H-C2. H-C2 positively regulates veinlet maybe through inhibition of inter-vein determinants in agreement with a model, whereby Notch and EGF signaling pathways cross-regulate vein pre-patterning.

Animals↗
PubMed2003

The role of Suppressor of Hairless in Notch mediated signalling during zebrafish somitogenesis.

Suppressor of Hairless (Su(H)) codes for a protein that interacts with the intracellular domain of Notch to activate the target genes of the Delta-Notch signalling pathway. We have cloned the zebrafish homologue of Su(H) and have analysed its function by morpholino mediated knockdown. While there are at least four notch and four delta homologues in zebrafish, there appears to be only one complete Su(H) homologue. We have analysed the function of Su(H) in the somitogenesis process and its influence on the expression of notch pathway genes, in particular her1, her7, deltaC and deltaD. The cyclic expression of her1, her7 and deltaC in the presomitic mesoderm is disrupted by the Su(H) knockdown mimicking the expression of these genes in the notch1a mutant deadly seven. deltaD expression is similarly affected by Su(H) knockdown like deltaC but shows in addition an ectopic expression in the developing neural tube. The inactivation of Su(H) in a fss/tbx24 mutant background leads furthermore to a clear breakdown of cyclic her1 and her7 expression, indicating that the Delta-Notch pathway is required for the creation of oscillation and not only for the synchronisation between neighbouring cells. The strongest phenotypes in the Su(H) knockdown embryos show a loss of all somites posterior to the first five to seven ones. This phenotype is stronger than the known amorphic phenotypes for notch1 (des) or deltaD (aei) in zebrafish, but mimicks the knockout phenotype of RBP-Jkappa gene in the mouse, which is the homologue of Su(H). This suggests that there is some functional redundancy among the Notch and Delta genes. This fact that the first five to seven somites are only weakly affected by Su(H) knockdown indicates that additional genetic pathways may be active in the specification of the most anterior somites.

Animals↗
PubMed1999

Overexpression of the m4 and malpha genes of the E(spl)-complex antagonizes notch mediated lateral inhibition.

Intercellular signalling mediated by Notch proteins is crucial to many cell fate decisions in metazoans. Its profound effects on cell fate and proliferation require that a complex set of responses involving positive and negative signal transducers be orchestrated around each instance of signalling. In Drosophila the basic-helix-loop-helix (bHLH) repressor encoding genes of the E(spl) locus are induced by Notch signalling and mediate some of its effects, such as suppression of neural fate. Here we report on a novel family of Notch responsive genes, whose products appear to act as antagonists of the Notch signal in the process of adult sensory organ precursor singularization. They, too, reside in the E(spl) locus and comprise transcription units E(spl) m4 and E(spl) malpha. Overexpression of these genes causes downregulation of E(spl) bHLH expression accompanied by cell autonomous overcommitment of sensory organ precursors and tufting of bristles. Interestingly, negative regulation of the Notch pathway by overexpression of E(spl) m4 and malpha is specific to the process of sensory organ precursor singularization and does not impinge on other instances of Notch signalling.

Amino Acid Sequence↗
PubMed1999

Fringe, Notch, and making developmental boundaries.

Multiple mechanisms are involved in positioning and restricting specialized dorsal-ventral border cells in the Drosophila wing, including modulation of Notch signaling by Fringe, autonomous inhibition by Notch ligands, and inhibition of Notch target genes by Nubbin. Recent studies have revealed that Fringe also modulates a Notch-mediated signaling process between dorsal and ventral cells in the Drosophila eye, establishing an organizer of eye growth and patterning along the dorsal-ventral midline. Fringe-dependent modulation of Notch signaling also plays a key role in Drosophila leg segmentation and growth. Lunatic Fringe has been shown to be required for vertebrate somitogenesis, where it appears to act as a crucial link between a molecular clock and the regulation of Notch signaling.

Animals↗
PubMed2002

Variations on the Notch pathway in neural development.

Notch signaling allows cells in contact to adopt different fates. Regulation of the Notch pathway allows for the same signaling mechanism to be used in a wide variety of contexts during development. Intracellular activities of the E3 ubiquitin ligases Sel-10 and Neuralized involve proteasome-dependent degradation in the regulation of Notch pathway activity. Extracellular manipulations of Notch by Fringe and Scabrous regulate the pathway by changing Notch interactions outside the cell. These regulatory mechanisms, along with many others, affect how Notch signaling activity influences cell fate determination.

Animals↗
PubMed2003

Notch signaling in lymphopoiesis.

Notch signaling regulates many cell fate decisions during development of multi-cellular organisms. Signals initiated by Notch influence a wide variety of processes that include lineage specification, cell survival and proliferation, and border formation. During development of the immune system, Notch has been shown to influence the fate of both hematopoietic stem cells (HSCs) and committed progenitors. Notch appears to play an especially important role in the development of cells that mediate acquired immunity where Notch influences multiple aspects of T and B cell development. In this review, we will focus on the potential functions of Notch signaling during lymphoid development.

Animals↗
PubMed2004

Anchoring notch genetics and biochemistry; structural analysis of the ankyrin domain sheds light on existing data.

Notch signaling is important in development and in human disease. Notch receptors regulate transcription through direct interactions with several proteins at the promoter regions of target genes. To understand the mechanism of Notch signaling, numerous deletion and mutagenesis studies have been carried out to identify functional domains in Notch, but domain definition and their role during the assembly of the transcriptionally active complex remains controversial. Recently reported biophysical and structural studies of the Notch ANK domain permit us to reevaluate the existing domain assignments and their predicted functional role, thereby providing further insight into the mechanism of Notch signaling.

Amino Acid Sequence↗
PubMed2003

Notch mediates TGF alpha-induced changes in epithelial differentiation during pancreatic tumorigenesis.

Notch signaling regulates cell fate decisions in a wide variety of adult and embryonic tissues. Here we show that Notch pathway components and Notch target genes are upregulated in invasive pancreatic cancer, as well as in pancreatic cancer precursors from both mouse and human. In mouse pancreas, ectopic Notch activation results in accumulation of nestin-positive precursor cells and expansion of metaplastic ductal epithelium, previously identified as a precursor lesion for pancreatic cancer. Notch is also activated as a direct consequence of EGF receptor activation in exocrine pancreas and is required for TGF alpha-induced changes in epithelial differentiation. These findings suggest that Notch mediates the tumor-initiating effects of TG alpha by expanding a population of undifferentiated precursor cells.

Animals↗
PubMed2001

Numb suppresses the negative complementation at the Notch locus of Drosophila melanogaster, suggesting a putative mechanism for negative complementation.

The mutant form of the intracellular asymmetrically localized Numb membrane-bound protein of Drosophila melanogaster suppresses the negative complementation of certain Abruptex (Ax) mutations of the Notch (N) locus encoding a transmembrane receptor protein in which the Ax mutations are mutations in the epidermal growth factor (EGF)-like repeats of the extracellular domain of the receptor. One model for how Ax mutants affect N function is that they are refractory to an antagonistic signal generated by an excess of N ligands. Genetically numb (nb) is an antagonist of N. In the absence of nb, cells follow the same fate as they would in the presence of a gain-of-function N allele, such as Ax. Numb has been shown to interact with the cytoplasmic domain of Notch. It is therefore suggested that numb counteracts the effect of Abruptex on Notch ligand binding, i.e. that Numb is an antagonist to the activation of the Notch signal generated by Notch ligands. Numb might accomplish this by interfering with the proteolytic cleavage of the Notch intracellular domain at the cell membrane. Thus, it seems possible that the mechanism of negative complementation of certain Ax mutants is the failure of this cleavage. Other possible mechanisms for negative complementation are also discussed.

Animals↗