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PubMed2005

Regulation of acquired immune system by notch signaling.

T- and B-cells are generated from hematopoietic stem cells through lymphoid intermediates. The interplay of intrinsic and extrinsic signals determines cell fate at the branch point for T- and B-cell lineages and at the post-commitment stage of lymphogenesis. The mature lymphocytes differentiate into effector/memory cells by antigen recognition, and those differentiation steps are also governed by a series of cell fate choices and survival signals, which allows cells to acquire distinct effector functions. The identification of the molecular details that dictate lymphocyte development and differentiation will improve understanding of acquired immune responses. Recent studies have revealed that Notch molecules, evolutionarily conserved transmembrane receptors, play key roles in lymphocyte development and differentiation. In this article, we review recent knowledge regarding the roles of Notch signaling in controlling both lymphocyte development and acquisition of effector functions.

Animals↗

PubMed2004

Notch1 and notch2 have opposite effects on embryonal brain tumor growth.

The role of Notch signaling in tumorigenesis can vary; Notch1 acts as an oncogene in some neoplasms, and a tumor suppressor in others. Here, we show that different Notch receptors can have opposite effects in a single tumor type. Expression of truncated, constitutively active Notch1 or Notch2 in embryonal brain tumor cell lines caused antagonistic effects on tumor growth. Cell proliferation, soft agar colony formation, and xenograft growth were all promoted by Notch2 and inhibited by Notch1. We also found that Notch2 receptor transcripts are highly expressed in progenitor cell-derived brain tumors such as medulloblastomas, whereas Notch1 is scarce or undetectable. This parallels normal cerebellar development, during which Notch2 is predominantly expressed in proliferating progenitors and Notch1 in postmitotic differentiating cells. Given the oncogenic effects of Notch2, we analyzed its gene dosage in 40 embryonal brain tumors, detecting an increased copy number in 15% of cases. Notch2 gene amplification was confirmed by fluorescence in situ hybridization in one case with extremely high Notch2 mRNA levels. In addition, expression of the Notch pathway target gene Hes1 in medulloblastomas was associated with significantly shorter patient survival (P = 0.01). Finally, pharmacological inhibition of Notch signaling suppresses growth of medulloblastoma cells. Our data indicate that Notch1 and Notch2 can have opposite effects on the growth of a single tumor type, and show that Notch2 can be overexpressed after gene amplification in human tumors.

Animals↗

PubMed1996

Expression patterns of Jagged, Delta1, Notch1, Notch2, and Notch3 genes identify ligand-receptor pairs that may function in neural development.

Notch genes encode receptors for a signaling pathway that regulates neurogenesis. The DSL (Delta/Serrate/lag-2) genes encode ligands that bind and activate Notch. In situ hybridization was used to determine the spatiotemporal expression of Notch1, Notch2, and Notch3, and the DSL ligands, Jagged and Delta 1, in an effort to identify potential ligand-receptor pairs that function during development of the rat nervous system. Here we describe both distinct and overlapping expression patterns for these genes in neural progenitors that form both the central and the peripheral nervous systems. The punctate expression patterns we detected for Jagged and Delta 1 are consistent with their role in mediating lateral inhibition, a process proposed to regulate neural determination. Furthermore, within the ventricular zone of the neural tube and retina, Jagged and Delta 1 were expressed in complementary regions, suggesting that different DSL-Notch combinations may direct the development of distinct neural subtypes.

Animals↗

PubMed2003

Expression of Wnt and Notch pathway genes in a pluripotent human embryonal carcinoma cell line and embryonic stem cell.

Embryonal carcinoma (EC) cells, the pluripotent stem cells of teratocarcinomas, show many similar-ities to embryonic stem (ES) cells. Since EC cells are malignant but their terminally differentiated derivatives are not, understanding the molecular mechanisms that regulate their differentiation maybe of value for diagnostic and therapeutic purposes. We have examined the expression of multiple components of two developmentally important cell-cell signalling pathways, Wnt and Notch, in the pluripotent human EC cell line, NTERA2, and the human ES cell line, H7. Both pathways have well-documented roles in controlling neurogenesis, a process that occurs largely in response to retinoicacid (RA) treatment of NTERA2 cultures and spontaneously in H7 cultures. In NTERA2, many ofthe genes tested showed altered transcriptional regulation following treatment with RA. These include members of the frizzled gene family (FZDI, FZD3, FZD4, FZD5, FZD6), encoding receptors forWnt proteins, the Frizzled Related Protein family (SFRPI, SFRP2, FRZB, SFRP4), encoding solubleWnt antagonists and also ligands and receptors of the Notch pathway (Dlkl, Jaggedl; Notchl, Notch2, Notch3). Few differences were found in the repertoire of Wnt and Notch pathway genes expressed by NTERA2 EC cells and H7 ES cells. We present a model in which interactions between and regulation of Wnt and Notch signalling are important in maintaining EC/ES stem cells and also controlling their differentiation.

Carcinoma, Embryonal↗

PubMed2003

Notch activity is required to maintain floorplate identity and to control neurogenesis in the chick hindbrain and spinal cord.

Notch signalling plays a major role in many invertebrate and vertebrate patterning systems. In this paper, we use high-titre, non-replicative pseudotype viruses to show that the two Notch ligands, Delta1 and Serrate1 (Jagged1), have differing activities in the developing chick spinal cord and hindbrain. In the walls of the neural tube, Serrate1 appears not to affect neurogenesis, in contrast to Delta1 which mediates lateral inhibition as elsewhere in the nervous system. In the floorplate we find that there is also a requirement for Notch, but with a different type of dependence on the two Notch ligands: cells with a floorplate character are lost when Notch activity is blocked with dominant-negative, truncated forms of either Delta1 or Serrate1. Our results are consistent with ligand-receptor specificity within the Notch signalling pathway, Serrate1 recognising selectively Notch2 (which is expressed in the floorplate), and Delta1 acting on both Notch2 and Notch1 (which is expressed in the walls of the neural tube).

Animals↗

PubMed2001

Defects in development of the kidney, heart and eye vasculature in mice homozygous for a hypomorphic Notch2 mutation.

The Notch gene family encodes large transmembrane receptors that are components of an evolutionarily conserved intercellular signaling mechanism. To assess the in vivo role of the Notch2 gene, we constructed a targeted mutation, Notch2(del1). Unexpectedly, we found that alternative splicing of the Notch2(del1) mutant allele leads to the production of two different in-frame transcripts that delete either one or two EGF repeats of the Notch2 protein, suggesting that this allele is a hypomorphic Notch2 mutation. Mice homozygous for the Notch2(del1) mutation died perinatally from defects in glomerular development in the kidney. Notch2(del1)/Notch2(del1 )mutant kidneys were hypoplastic and mutant glomeruli lacked a normal capillary tuft. The Notch ligand encoded by the Jag1 gene was expressed in developing glomeruli in cells adjacent to Notch2-expressing cells. We show that mice heterozygous for both the Notch2(del1) and Jag1(dDSL) mutations exhibit a glomerular defect similar to, but less severe than, that of Notch2(del1)/Notch2(del1 )homozygotes. The co-localization and genetic interaction of Jag1 and Notch2 imply that this ligand and receptor physically interact, forming part of the signal transduction pathway required for glomerular differentiation and patterning. Notch2(del1)/Notch2(del1 )homozygotes also display myocardial hypoplasia, edema and hyperplasia of cells associated with the hyaloid vasculature of the eye. These data identify novel developmental roles for Notch2 in kidney, heart and eye development.

Alleles↗

PubMed1995

Differential expression of Notch1 and Notch2 in developing and adult mouse brain.

The Notch gene encodes a large transmembrane protein, and is required for the correct differentiation of both neural and non-neural tissues in Drosophila. Mammals have more than one Notch gene homolog, e.g. Notch1 and Notch2. Here, in order to determine the role of Notch genes in the mouse nervous system, we used in situ hybridization to study the expression of the Notch1 and -2 genes through mouse embryogenesis and into adulthood. The expression of Notch1 and Notch2 differed throughout development. Notch2 was expressed in the embryonic ventricular zone, the postnatal ependymal cells, and the choroid plexus throughout embryonic and postnatal development. Notch1 was also expressed in the ventricular zone between embryonic days 10 and 14, but its expression decreased gradually as embryos developed. The postnatal mouse brain strongly expressed Notch2, but not Notch1, in the granular cell layer of hippocampal dentate gyrus, where neurogenesis continues even in adult rodents. The most remarkable finding was the detection of a strong signal for Notch2 mRNA in two circumventricular organs: the subfornical organ and the area postrema. The receptor encoded by the Notch2 gene, which is located in these areas, may respond to unknown ligands in CSF. This putative receptor may participate in signal transduction by way of both neural and humoral links. These data suggest that Notch2, rather than Notch1, is related not only to development, but also to some postnatal functions of mouse central nervous system.

Animals↗

PubMed2006

Expression of the Notch signaling pathway and effect on exocrine cell proliferation in adult rat pancreas.

When pancreatic tissue is injured after duct obstruction, acinoductal metaplasia is observed. Similar metaplastic changes occur when exocrine pancreatic cells are isolated and cultured. We demonstrate that under these experimental conditions the exocrine acinar cells lose their differentiated characteristics: expression of the acinar transcription factors p48/Ptf1alpha and Mist1 is decreased or lost, whereas expression of the embryonic transcription factor Pdx1 is increased. The receptors Notch1 and Notch2, members of the DSL family of Notch ligands, and the target genes in the Notch-signaling pathway Hes1, Hey1, and Hey2 become strongly up-regulated. We noted also reduced expression of Sel1L, a Notch repressor that is normally highly expressed in exocrine pancreas. Stimulation of Notch by its ligand Jagged1 diminished the proliferation of cultured metaplastic exocrine cells. Chemical inhibition of Notch signaling resulted in increased proliferation and induction of the cell-cycle regulator p21Cip1. This effect seems to be Hes1-independent and mainly coincides with decreased Hey1 and Hey2 mRNA expression. In conclusion, we demonstrate that during acinoductal metaplasia the Notch-signaling pathway is activated concomitantly with changes in transcription factor expression of pancreatic acinar cells. In addition, we show that Notch signaling is implicated in the suppression of proliferation of these metaplastic exocrine cells. The latter may be important in protection from neoplastic transformation.

Animals↗

PubMed2006

Pivotal role of Notch signaling in regulation of erythroid maturation and proliferation.

Notch signaling plays an important role in cell fate decisions in developmental systems. To clarify its role in committed hematopoietic progenitor cells, we investigated the effects of Notch signaling in erythroid colony forming cells (ECFCs) generated from peripheral blood. ECFCs express Notch receptors, Notch1 and Notch2, and Notch ligands Delta1, Delta4, and Jagged1. When we assayed the effects of Notch ligands on erythroid maturation by flow cytometry, we found that immobilized Delta1 and immobilized Delta4 in particular inhibited maturation, whereas Jagged1 had no effect. In addition, Delta4 inhibited proliferation without reducing cell viability. Increases in expression levels of the Notch target gene hairy enhancer of split (HES) -1 were evident by real-time PCR after stimulation with immobilized Delta4. The effect of soluble Delta4 on expression of HES-1 was less pronounced than that seen with the immobilized form, indicating that all surface-bound ligands are important for effective signal transduction. When ECFCs were cultured in the presence of soluble Delta4 at a low cell concentration, erythroid maturation was slightly inhibited, but at a high concentration, maturation was promoted via competition of soluble Delta4 with endogenous ligands. These results indicate a pivotal role of Notch signaling in regulating erythroid maturation and proliferation, and further suggest that cell-cell interactions modulate growth of erythroid progenitor cells via Notch system.

Base Sequence↗

PubMed2002

Chimeric analysis of Notch2 function: a role for Notch2 in the development of the roof plate of the mouse brain.

Notch proteins are transmembrane receptors involved in cell-fate determination throughout development. Targeted disruption of either the Notch1 or Notch2 gene in mice results in embryonic lethality around embryonic day (E) 10.5 with widespread cell death. Although Notch1-deficient mice show disorganized somitogenesis, Notch2 mutants did not show definitive abnormalities in any tissue expressing high levels of the Notch2 gene, including the central nervous system. To study Notch2 function in development beyond the embryonic lethal stage, we performed chimeric analysis between Notch2 mutant and wild-type mouse embryos. Chimeric embryos developed normally and homozygous Notch2 mutant-specific cell death was not observed. Although chimeric embryos showed normal mosaicism until E9.5 in all tissues studied to date, Notch2 homozygous mutant cells failed to contribute to formation of the roof plate of the diencephalon and mesencephalon at later developmental stages, when Notch2 is normally expressed at high levels at there. Furthermore, Notch2 heterozygous mutant cells were also excluded from the roof plate of the chimera, however, Notch2 heterozygous mutant mice developed normally. We also showed that Wnt-1 and Mash1 expression patterns at the roof plate were disorganized in Notch2 homozygous mutant embryos. These results indicate that Notch2 plays an important role in development of the roof plate of the diencephalon and mesencephalon, and suggest that cellular rearrangement is involved in this process.

Animals↗

PubMed2003

Notch2 protein distribution in human teeth under normal and pathological conditions.

Notch signaling is essential for the appropriate differentiation of many cell types during development and, furthermore, is implicated in a variety of human diseases. Previous studies have shown that although the Notch1, -2, and -3 receptors are expressed in developing and injured rodent teeth, Notch2 expression was predominant after a lesion. To pursue the role of the Notch pathway in tooth development and disease, we have analyzed the expression of the Notch2 protein in embryonic and adult wounded human teeth. During the earlier stages of tooth development, the Notch2 protein was expressed in the epithelium, but was absent from proliferating cells of the inner enamel epithelium. At more advanced stages, Notch2 was expressed in the enamel-producing ameloblasts, while it was absent in mesenchyme-derived odontoblasts that synthesize the dentin matrix. Although Notch2 was not expressed in the pulp of adult intact teeth, it was reexpressed during dentin repair processes in odontoblasts and subodontoblastic cells. Transforming growth factor beta-1, which stimulates odontoblast differentiation and hard tissue formation after dental injury, downregulated Notch2 expression in cultured human dental slices, in vitro. These observations are consistent with the notion that Notch signaling is an important element in dental physiological and pathogenic conditions.

Adult↗

PubMed2000

Dynamic Lunatic fringe expression is correlated with boundaries formation in developing mouse teeth.

The formation of boundaries is a fundamental organizing principle during development. The Notch signalling pathway regulates this developmental patterning mechanism in many tissues. Recent data suggest that Notch receptors are involved in boundary determination during odontogenesis. It remains, however, uncertain if other components of the Notch pathway are also important for compartmental lineage restrictions in teeth. Here we report on the expression of the Lunatic fringe gene, which encodes a secreted signalling molecule regulating the Notch pathway, during the development of mouse teeth. Lunatic fringe is expressed in both epithelial and mesenchymal components of the developing molar. The expression pattern of Lunatic fringe in the epithelium is complementary to that of the Notch receptors. Lunatic fringe is asymmetrically expressed in the incisor epithelium during its antero-posterior rotation. This expression pattern defines the lingual comportment of the incisor epithelium whereas the labial comportment is defined by Notch2 expression.

Animals↗

PubMed2004

Expression of notch receptors and ligands in the adult gut.

The Notch signaling pathway has become recognized as a vitally important pathway in regulating proliferative/differentiative decisions and cell fate. To explore the involvement of the Notch pathway in adult gut, we investigated the expression of Notch receptors and their ligands by Northern blotting and in situ hybridization. Notch receptors and ligands were expressed in both proliferative and post-mitotic cells throughout adult rat gut, variously in epithelial, immune, and endothelial cells. Expression of Notch1, Jagged1, and Jagged2 frequently overlapped, whereas Notch2 expression was restricted to specific crypt cells, the lamina propria of the large intestine, and Peyer's patch lymphocytes. We propose that the expression of multiple Notch receptors and ligands in a range of different intestinal cell types indicates that this signaling pathway underpins many of the processes involved in the maintenance and function of the adult gut.

Animals↗

PubMed1999

Reactivation of Delta-Notch signaling after injury: complementary expression patterns of ligand and receptor in dental pulp.

The evolutionarily conserved Notch-mediated intercellular signaling pathway is essential for proper embryonic development of many tissues and organs. Recent data suggest that Notch receptors and their membrane-bound ligands Delta and Serrate are involved in both patterning and cell fate determination during odontogenesis. It remains, however, uncertain if Notch signaling is important for tooth homeostasis and regeneration. Here we report on the expression of Notch receptors and the Delta1 ligand in dental pulp of normal and injured adult rat teeth. Notch receptors were absent from normal adult dental tissues, whereas expression was upregulated after injury. In injured teeth, Notch2 was expressed in mesenchymal cells of the pulp both close to the site of injury (i.e., in the dental crown) and at a distance from it (i.e., in the dental roots), Notch3 expression was mainly associated with vascular structures, while Notch1 expression was restricted to few pulpal cells close to the lesion. None of them was expressed in odontoblasts. Expression of Delta1 was upregulated in odontoblasts of the injured teeth, as well as in vascular structures. These results demonstrate the reactivation of the Notch signaling pathway during wound healing and, furthermore, highlight the similarity between developmental and regenerative processes.

Animals↗

PubMed2000

Notch signaling enhances survival and alters differentiation of 32D myeloblasts.

The Notch transmembrane receptors play important roles in precursor survival and cell fate specification during hematopoiesis. To investigate the function of Notch and the signaling events activated by Notch in myeloid development, we expressed truncated forms of Notch1 or Notch2 proteins that either can or cannot activate the core binding factor 1 (CBF1) in 32D (clone 3) myeloblasts. 32D cells proliferate as blasts in the presence of the cytokines, GM-CSF or IL-3, but they initiate differentiation and undergo granulopoiesis in the presence of granulocyte CSF (G-CSF). 32D cells expressing constitutively active forms of Notch1 or Notch2 proteins that signal through the CBF1 pathway maintained significantly higher numbers of viable cells and exhibited less cell death during G-CSF induction compared with controls. They also displayed enhanced entry into granulopoiesis, and inhibited postmitotic terminal differentiation. In contrast, Notch1 constructs that either lacked sequences necessary for CBF1 binding or that failed to localize to the nucleus had little effect. Elevated numbers of viable cells during G-CSF treatment were also observed in 32D cells overexpressing the basic helix-loop-helix protein (bHLH), HES1, consistent with activation of the CBF1 pathway. Taken together, our data suggest that Notch signaling enhances 32D cell survival, promotes entry into granulopoiesis, and inhibits postmitotic differentiation through a CBF1-dependent pathway.

Animals↗

PubMed2001

Distinct and regulated expression of Notch receptors in hematopoietic lineages and during myeloid differentiation.

Hematopoietic development is a delicate balance of cell fate decisions in multipotent cells between self-renewal and differentiation. In multiple developmental systems, the Notch receptors are important factors regulating these processes. Hematopoietic progenitor cells have been shown to express Notch1, and studies with an activated intracellular form has revealed a functional role. To assess the function of other Notch members in hematopoiesis, we investigated the expression pattern of Notch1, Notch2, and Notch3 in hematopoietic lineages at the level of RNA and protein. We demonstrate that Notch1 and Notch2 are expressed in multiple lineages, and that Notch1 in particular appears to be regulated during myeloid differentiation. Notch1 was up-regulated and expressed at high levels in adherent macrophages. Mast cells expressed only low levels of Notch1 mRNA whereas Notch2 mRNA was highly expressed. In addition we could detect Notch3 mRNA and protein in cell lines representing mast cell progenitors. These expression patterns imply that the different Notch genes may have very distinct functions during hematopoiesis, and that Notch3 could be a specific regulator of mast cell development. The finding that Notch1 was up-regulated in the adherent cells developing from a multipotent progenitor cell line suggests that this protein may posses dual functions in hematopoiesis, i.e. at the stage of cell fate decision, and at the maturation stage of monocytes when adhesion to the specific microenvironment is accomplished.

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↗

PubMed2007

Asymmetric localization of Notch2 on the microvillous surface in choroid plexus epithelial cells.

Notch family molecules are transmembrane receptors that play various roles in contact-dependent cell-cell interactions in a wide range of organs. In the brain, Notch2, but not the other members of Notch, is expressed in the choroid plexus at an exceptionally high level. We immunohistochemically examined the cellular and subcellular localization of Notch2 protein in the choroid plexus using confocal and electron microscopy. Unexpectedly, Notch2 was asymmetrically localized on the microvillous surface of epithelial cells in the choroid plexus of both postnatal and adult rats. This localization pattern of Notch2 suggests its novel and unknown role independent of contact with adjacent cells in the choroid plexus. In organotypic cultures of the choroid plexus, the addition of anti-Notch2 antibody resulted in deformation of microvilli in epithelial cells, which suggests a role of Notch2 in the maintenance of the microvillous structure in choroid plexus epithelial cells.

Animals↗