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PubMed2005

Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially regulate activation of peripheral T helper cells.

The Notch pathway is involved in cell differentiation processes in various organs and at several developmental stages. The importance of Notch for early T lymphocyte development is well established. Recently, Notch has been implicated in directing naive T helper cell differentiation towards the Th1, Th2 or regulatory T cell lineages. However, the molecular events underlying these processes are poorly understood. We show that the Notch ligands Delta-like1, Delta-like4 and Jagged1 differentially affect early T cell activation and proliferation following T cell receptor cross-linking. Delta-like1 and Jagged1 induce a dose-dependent inhibition of early activation markers CD69 and CD25, as well as inhibition of proliferation after anti-CD3 stimulation of purified CD4+ T cells. Similarly, the rapid activation of transcription factors NF-AT, AP-1 and NF-kappaB is suppressed. In contrast, triggering of Notch by Delta-like4 enhances T cell activation and proliferation. The observed effects are dependent on simultaneous cross-linking of TCR and Notch but independent of gamma-secretase-mediated cleavage of Notch. These data suggest direct interference between Notch and early TCR signal transduction events, independent of the classical Notch pathway via release of the Notch intracellular domain. A Notch-mediated alteration of TCR signaling strength may contribute to the recently described modulation of naïve T cell differentiation by Notch ligands.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Interactions between muscle fibers and segment boundaries in zebrafish.

The most obvious segmental structures in the vertebrate embryo are somites: transient structures that give rise to vertebrae and much of the musculature. In zebrafish, most somitic cells give rise to long muscle fibers that are anchored to intersegmental boundaries. Therefore, this boundary is analogous to the mammalian tendon in that it transduces muscle-generated force to the skeletal system. We have investigated interactions between somite boundaries and muscle fibers. We define three stages of segment boundary formation. The first stage is the formation of the initial epithelial somite boundary. The second "transition" stage involves both the elongation of initially round muscle precursor cells and somite boundary maturation. The third stage is myotome boundary formation, where the boundary becomes rich in extracellular matrix and all muscle precursor cells have elongated to form long muscle fibers. It is known that formation of the initial epithelial somite boundary requires Notch signaling; vertebrate Notch pathway mutants show severe defects in somitogenesis. However, many zebrafish Notch pathway mutants are homozygous viable suggesting that segmentation of their larval and adult body plans at least partially recovers. We show that epithelial somite boundary formation and slow-twitch muscle morphogenesis are initially disrupted in after eight (aei) mutant embryos (which lack function of the Notch ligand, DeltaD); however, myotome boundaries form later ("recover") in a Hedgehog-dependent fashion. Inhibition of Hedgehog-induced slow muscle induction in aei/deltaD and deadly seven (des)/notch1a mutant embryos suggests that slow muscle is necessary for myotome boundary recovery in the absence of initial epithelial somite boundary formation. Because we have previously demonstrated that slow muscle migration triggers fast muscle cell elongation in zebrafish, we hypothesize that migrating slow muscle facilitates myotome boundary formation in aei/deltaD mutant embryos by patterning coordinated fast muscle cell elongation. In addition, we utilized genetic mosaic analysis to show that somite boundaries also function to limit the extent to which fast muscle cells can elongate. Combined, our results indicate that multiple interactions between somite boundaries and muscle fibers mediate zebrafish segmentation.

Animals↗
PubMed1999

A widespread and early requirement for a novel Notch function during Drosophila embryogenesis.

The Notch pathway plays a key role in the formation of many tissues and cell types in Metazoans. We recently showed that Notch acts in two pathways to determine muscle precursor fates. The first is the "standard" Notch pathway, in which Delta activates the Notch receptor, which then translocates into the nucleus in conjunction with Su(H) to reprogram transcription patterns and bring about changes in cell fates. The second pathway is poorly defined, but known to be independent of the ligands and downstream effectors of the standard pathway. The standard pathway is required in many different developmental contexts and we wondered if there was also a general requirement for the novel pathway. Here we show that the novel Notch pathway is required for the development of each of five examined cell types. These results indicate that the novel pathway is a widespread and fundamental component of Notch function. We further show that both Notch pathways operate in the differentiation of the same cell types. In such cases, the novel pathway acts first and appears to set up or limit the size of equivalence groups. The standard pathway then acts within the equivalence groups to limit individual cell fates.

Animals↗
PubMed2005

Integrinalpha5 and delta/notch signaling have complementary spatiotemporal requirements during zebrafish somitogenesis.

Somitogenesis is the process by which the segmented precursors of the skeletal muscle and vertebral column are generated during vertebrate embryogenesis. While somitogenesis appears to be a serially homologous, reiterative process, we find that there are differences between the genetic control of early/anterior and late/posterior somitogenesis. We demonstrate that point mutations can cause segmentation defects in either the anterior, middle, or posterior somites in the zebrafish. We find that mutations in zebrafish integrinalpha5 disrupt anterior somite formation, giving a phenotype complementary to the posterior defects seen in the notch pathway mutants after eight/deltaD and deadly seven/notch1a. Double mutants between the notch pathway and integrinalpha5 display somite defects along the entire body axis, with a complete loss of the mesenchymal-to-epithelial transition and Fibronectin matrix assembly in the posterior. Our data suggest that notch- and integrinalpha5-dependent cell polarization and Fibronectin matrix assembly occur concomitantly and interdependently during border morphogenesis.

Amino Acid Sequence↗
PubMed2006

Inhibition of nuclear factor kappab activity by genistein is mediated via Notch-1 signaling pathway in pancreatic cancer cells.

Pancreatic cancer remains the fourth most common cause of cancer related death in the United States. Therefore, novel strategies for the prevention and treatment are urgently needed. Genistein is a prominent isoflavonoid found in soy products and has been proposed to be responsible for lowering the rate of pancreatic cancer in Asians. However, the molecular mechanism(s) by which genistein elicits its effects on pancreatic cancer cells has not been fully elucidated. We have previously shown that genistein induces apoptosis and inhibits the activation of nuclear factor kappaB (NF-kappaB) pathway. Moreover, Notch signaling is known to play a critical role in maintaining the balance between cell proliferation, differentiation and apoptosis, and thereby may contribute to the development of pancreatic cancer. Hence, in our study, we investigated whether there is any cross talk between Notch and NF-kappaB during genistein-induced apoptosis in BxPC-3 pancreatic cancer cells. We used multiple cellular and molecular approaches such as MTT assay, apoptosis assay, gene transfection, Western blotting and EMSA for measuring DNA binding activity of NF-kappaB. We found that genistein inhibits cell growth and induces apoptotic processes in BxPC-3 pancreatic cancer cells. This was partly due to inhibition of Notch-1 activity. BxPC-3 cells transfected with Notch-1 cDNA showed induction of NF-kappaB activity, and this was inhibited by genistein treatment. From these results, we conclude that the inhibition of Notch-1 and NF-kappaB activity and their cross talk provides a novel mechanism by which genistein inhibits cell growth and induces apoptotic processes in pancreatic cancer cells.

Antineoplastic Agents↗
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

Gamma -secretase inhibitors repress thymocyte development.

A major therapeutic target in the search for a cure to the devastating Alzheimer's disease is gamma-secretase. This activity resides in a multiprotein enzyme complex responsible for the generation of Abeta42 peptides, precipitates of which are thought to cause the disease. Gamma-secretase is also a critical component of the Notch signal transduction pathway; Notch signals regulate development and differentiation of adult self-renewing cells. This has led to the hypothesis that therapeutic inhibition of gamma-secretase may interfere with Notch-related processes in adults, most alarmingly in hematopoiesis. Here, we show that application of gamma-secretase inhibitors to fetal thymus organ cultures interferes with T cell development in a manner consistent with loss or reduction of Notch1 function. Progression from an immature CD4-/CD8- state to an intermediate CD4+/CD8+ double-positive state was repressed. Furthermore, treatment beginning later at the double-positive stage specifically inhibited CD8+ single-positive maturation but did not affect CD4+ single-positive cells. These results demonstrate that pharmacological gamma-secretase inhibition recapitulates Notch1 loss in a vertebrate tissue and present a system in which rapid evaluation of gamma-secretase-targeted pharmaceuticals for their ability to inhibit Notch activity can be performed in a relevant context.

Amyloid Precursor Protein Secretases↗
PubMed2000

Two different activities of Suppressor of Hairless during wing development in Drosophila.

The Notch pathway plays a crucial and universal role in the assignation of cell fates during development. In Drosophila, Notch is a transmembrane protein that acts as a receptor of two ligands Serrate and delta. The current model of Notch signal transduction proposes that Notch is activated upon binding its ligands and that this leads to the cleavage and release of its intracellular domain (also called Nintra). Nintra translocates to the nucleus where it forms a dimeric transcription activator with the Su(H) protein. In contrast with this activation model, experiments with the vertebrate homologue of Su(H), CBF1, suggest that, in vertebrates, Nintra converts CBF1 from a repressor into an activator. Here we have assessed the role of Su(H) in Notch signalling during the development of the wing of Drosophila. Our results show that, during this process, Su(H) can activate the expression of some Notch target genes and that it can do so without the activation of the Notch pathway or the presence of Nintra. In contrast, the activation of other Notch target genes requires both Su(H) and Nintra, and, in the absence of Nintra, Su(H) acts as a repressor. We also find that the Hairless protein interacts with Notch signalling during wing development and inhibits the activity of Su(H). Our results suggest that, in Drosophila, the activation of Su(H) by Notch involve the release of Su(H) from an inhibitory complex, which contains the Hairless protein. After its release Su(H) can activate gene expression in absence of Nintra.

Animals↗
PubMed2005

Notch: a unique therapeutic target for immunomodulation.

Under normal circumstances, the adaptive immune response to either self or harmless antigens is kept under tight control by a combination of deletion mechanisms in the central immune system, and by a system of regulatory cells in the periphery. Together, these control mechanisms enforce a state referred to as immunological tolerance. Breakdown of these mechanisms lead to a variety of immunological disease states involving persistent immune-mediated pathologies. Whereas the processes inducing central tolerance in the immune system are well documented, the mechanisms by which peripheral regulatory cells function are still unclear. Recent publications have reported an unexpected role for the Notch pathway, itself a classical regulator of cell fate, in the development of regulatory T cells. These exciting data demonstrate that Notch signals modulate events downstream of the T cell receptor, diverting T cell differentiation into alternative fates which regulate immune responses in an antigen-specific manner. The Notch pathway is, therefore, uniquely positioned in the developmental pathways leading to regulatory T cells. In this review, the authors discuss the data surrounding the role of Notch in the peripheral immune system, and discuss how this pathway might be manipulated for the treatment of immunological disorders.

Animals↗
PubMed1997

Suppressor of Hairless-independent events in Notch signaling imply novel pathway elements.

The Notch (N) pathway defines an evolutionarily conserved cell signaling mechanism that governs cell fate choices through local cell interactions. The ankyrin repeat region of the Notch receptor is essential for signaling and has been implicated in the interactions between Notch and two intracellular elements of the pathway: Deltex (Dx) and Suppressor of Hairless (Su(H)). Here we examine directly the function of the Notch cdc10/ankyrin repeats (ANK repeats) by transgenic and biochemical analysis. We present evidence implicating the ANK repeats in the regulation of Notch signaling through homotypic interactions. In vivo expression of the Notch ANK repeats reveals a cell non-autonomous effect and elicits mutant phenotypes that indicate the existence of novel downstream events in Notch signaling. These signaling activities are independent of the known effector Su(H) and suggest the existence of yet unidentified Notch pathway components.

Animals↗
PubMed2005

A novel hes5/hes6 circuitry of negative regulation controls Notch activity during neurogenesis.

HES transcriptional repressors are important components of the Notch pathway that regulates neurogenesis from Drosophila to vertebrates. These proteins are normally induced by Notch activity and inhibit neural commitment by antagonizing the activity of proneural genes. We describe here four chick hes genes that are expressed during neurogenesis: three hes5-like genes (hes5-1, hes5-2 and hes5-3) and one hes6-like (hes6-2). We show that hes6-2 represses transcription of the hes5 genes, thus functioning as a negative regulator of Notch signaling. Conversely, hes6-2 may be repressed by hes5 activity. In cells committing to differentiation, we find that hes6-2 is up-regulated by proneural genes and contributes to the proneural program of neuronal commitment by preventing Notch activity in these cells. In neural progenitors, Notch signaling produces an initial burst of hes5 activity, which represses hes6-2. However, as hes5 transcription declines due to negative auto-regulation, hes6-2 may become active and inhibit the remaining hes5 activity to end Notch signaling. These cells can then enter a new cycle of fate decisions and will be kept as progenitors if a new pulse of Notch activity occurs. Maintenance of progenitors during vertebrate neurogenesis therefore requires that these cells go through successive cycles of Notch activity. We propose that the hes5/hes6 circuitry of negative cross-regulations is a conserved feature of the Notch pathway that underlies these cycles in neural progenitors.

Amino Acid Sequence↗
PubMed2005

Role of glial cell line-derived neurotrophic factor in germ-line stem cell fate.

The overall goal of this study is to unravel the role(s) played by glial cell line-derived neurotrophic factor (GDNF) in the fate of spermatogonial stem cells. There is great interest in the biology of spermatogonial stem cells, or A(single) spermatogonia, because of their importance in the treatment of infertility, the development of contraceptives, and the understanding of the etiology of testicular cancer, particularly seminoma. In the mouse, spermatogonial stem cells express GFRalpha-1, the receptor for GDNF, and respond to this growth factor in vivo and in vitro. GDNF is produced by the adjacent Sertoli cells, which are part of the germ-line stem cell niche in vertebrates. We specifically isolated GFRalpha-1-positive spermatogonia using an immunomagnetic bead technique. We then stimulated the cells with 100 ng/mL of rGDNF for 10 hours; unstimulated cells served as negative controls. Microarray analysis, immunocytochemistry, and Western blotting revealed that Numb, a regulator of the Notch pathway, is upregulated by GDNF in spermatogonial stem cells. There are indications that in rats, mice, and humans, the Notch pathway promotes spermatogonial differentiation. We observed that an increase in Numb expression is concomitant with Notch degradation in these cells. Thus, through Numb, GDNF might inhibit differentiation and allows the maintenance of the stem cell pool in the mouse seminiferous epithelium.

Animals↗
PubMed2003

Conversion of biliary system to pancreatic tissue in Hes1-deficient mice.

The biliary system, pancreas and liver all develop from the nearby foregut at almost the same time in mammals. The molecular mechanisms that determine the identity of each organ in this complex area are unknown. Hes1 encodes the basic helix-loop-helix protein Hes1 (ref. 1), which represses positive basic helix-loop-helix genes such as Neurog3 (ref. 3). Expression of Hes1 is controlled by the evolutionarily conserved Notch pathway. Hes1 operates as a general negative regulator of endodermal endocrine differentiation, and defects in Notch signaling lead to accelerated pancreatic endocrine differentiation. Mutations in JAG1, encoding a Notch ligand, cause the Alagille syndrome in humans, characterized by poor development of the biliary system, suggesting that the Notch pathway is also involved in normal biliary development. Here we show that Hes1 is expressed in the extrahepatic biliary epithelium throughout development and that Hes1-deficient mice have gallbladder agenesis and severe hypoplasia of extrahepatic bile ducts. Biliary epithelium in Hes1-/- mice ectopically expresses the proendocrine gene Neurog3 (refs. 12,13), differentiates into endocrine and exocrine cells and forms acini and islet-like structures in the mutant bile ducts. Thus, biliary epithelium has the potential for pancreatic differentiation and Hes1 determines biliary organogenesis by preventing the pancreatic differentiation program, probably by directly repressing transcription of Neurog3.

Animals↗
PubMed2003

Differential regulation of Notch signal transduction in leukaemia and lymphoma cells in culture.

The transduction of Notch signal plays an intricate role in cell differentiation and pathogenesis of haematological malignancies as well as in certain congenital conditions. We found no genomic changes in either gene in 34 leukaemic samples and 25 leukaemia and lymphoma cell lines. The functionality of Notch signalling was tested using HES1 gene activation. We show that Notch signalling is differentially regulated in T-acute lymphoblastic leukaemia (ALL) and B-lymphoma cells. The Notch pathway is intact in a majority of B-lymphoma cell lines, but EBNA2, which mimics notch function, can occasionally activate the pathway. In contrast, the Notch pathway is constitutively active in T-ALL. This is the first demonstration of a distinction between B-lymphomas and T-cell leukaemias in the functioning of the Notch-signalling pathway. This might be related to their pathogenesis.

Cell Line, Tumor↗
PubMed2006

Notch1 and IL-7 receptor interplay maintains proliferation of human thymic progenitors while suppressing non-T cell fates.

Notch signaling is critical for T cell development of multipotent hemopoietic progenitors. Yet, how Notch regulates T cell fate specification during early thymopoiesis remains unclear. In this study, we have identified an early subset of CD34high c-kit+ flt3+ IL-7Ralpha+ cells in the human postnatal thymus, which includes primitive progenitors with combined lymphomyeloid potential. To assess the impact of Notch signaling in early T cell development, we expressed constitutively active Notch1 in such thymic lymphomyeloid precursors (TLMPs), or triggered their endogenous Notch pathway in the OP9-Delta-like1 stroma coculture. Our results show that proliferation vs differentiation is a critical decision influenced by Notch at the TLMP stage. We found that Notch signaling plays a prominent role in inhibiting non-T cell differentiation (i.e., macrophages, dendritic cells, and NK cells) of TLMPs, while sustaining the proliferation of undifferentiated thymocytes with T cell potential in response to unique IL-7 signals. However, Notch activation is not sufficient for inducing T-lineage progression of proliferating progenitors. Rather, stroma-derived signals are concurrently required. Moreover, while ectopic IL-7R expression cannot replace Notch for the maintenance and expansion of undifferentiated thymocytes, Notch signals sustain IL-7R expression in proliferating thymocytes and induce IL-7R up-regulation in a T cell line. Thus, IL-7R and Notch pathways cooperate to synchronize cell proliferation and suppression of non-T lineage choices in primitive intrathymic progenitors, which will be allowed to progress along the T cell pathway only upon interaction with an inductive stromal microenvironment. These data provide insight into a mechanism of Notch-regulated amplification of the intrathymic pool of early human T cell progenitors.

Animals↗
PubMed2001

Scalloped and strawberry notch are target genes of Notch signaling in the context of wing margin formation in Drosophila.

The Notch pathway regulates the differentiation of many cell types throughout development of higher metazoa. Different cellular responses are elicited through specific activation of distinct Notch target genes. In the Drosophila wing, for example, the cut gene is activated by Notch signaling along the dorso-ventral boundary but, as we show here, not in other cell types. We identify additional regulatory components, scalloped and strawberry notch, that are targets of the Notch pathway specifically within the wing anlagen. As suggested by physical interactions, these proteins could be co-factors of the cut trans-regulator Vestigial. Additional regulatory input comes from the Wingless pathway. Our data support a model, whereby context specific involvement of distinct co-regulators modulates Notch target gene activation.

Alleles↗
PubMed2001

Neuralized is essential for a subset of Notch pathway-dependent cell fate decisions during Drosophila eye development.

Neuralized (neur) is a neurogenic mutant of Drosophila in which many signaling events mediated by the Notch (N) receptor are disrupted. Here, we analyze the role of neur during eye development. Neur is required in a cell-autonomous fashion to restrict R8 and other photoreceptor fates and is involved in lateral inhibition of interommatidial bristles but is not required for induction of the cone cell fate. The latter contrasts with the absolute requirement for Suppressor of Hairless and the Enhancer of split-Complex for cone cell induction. Using gain-of-function experiments, we further demonstrate that ectopic wild-type and truncated Neur proteins can interfere with multiple N-controlled aspects of eye development, including both neur-dependent and neur-independent processes.

Animals↗
PubMed2003

Notch and cancer: best to avoid the ups and downs.

The Notch pathway is known for its multiple important roles in development and tissue homeostasis, and it can be subverted during oncogenic transformation. Two recent studies add to our understanding of Notch in cancer biology in contrasting ways, by showing novel mechanisms of Notch pathway activation in cancer cells, and by indicating that in some circumstances, Notch can behave as a tumor suppressor.

Animals↗