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PubMed2006

Expression of Notch1 and Hes5 in the developing olfactory epithelium.

CONCLUSION: Notch signaling pathway may play an important role in the development of the olfactory epithelium (OE). Objectives. To elucidate whether the Notch signaling pathway mediates the developmental processes in the developing OE. MATERIALS AND METHODS: The expression of Notch1 and Hes5 in the developing OE of mice with ages ranging from embryonic day (E) 11 to postnatal day (PN) 14 was examined. RESULTS: As detected by in situ hybridization, Notch1 was expressed in scattered cells located in the basal portion of the embryonic OE and later in the cell layer adjacent to the basal lamina from E11 to PN14. Hes5 was expressed in scattered cells located in the basal portion of the embryonic OE from E11. However, at the late embryonic stage, the number of Hes5-positive cells decreased and after birth distinct Hes5-positive cells were not observed in the OE.

Animals↗
PubMed2004

Identification and characterization of human HES2, HES3, and HES5 genes in silico.

MMTV induces the mouse mammary tumor through the dysregulation of Notch, Wnt, or Fgf signaling pathway. Activation of Notch signaling pathway leads to transcriptional activation of Hes family genes through the interaction between Notch intracellular domain and RBPSUH (CSL). Hes family proteins are mammalian homologs of Drosophila Hairy and Enhancer of split. Hes family of transcriptional repressors with basic Helix-loop-helix (bHLH) and Orange domains are implicated in the cell fate determination of stem cells (or precursor cells) by suppressing the expression of tissue-specific transcriptional activators. Human HES1, HES4, HES6, and HES7 genes have been reported by other groups. Here, we identified and characterized human HES2, HES3 and HES5 genes by using bioinformatics. FLJ33803 (AK091122.1) was the representative human HES2 cDNA. HES2 gene, encoding a 173-aa protein, was located within human genome sequence AL031848.11. HES3 gene, encoding a 186-aa protein, was identified within human genome sequence AL031847.17. HES5 gene, encoding a 166-aa protein, was identified within human genome sequence AL139246.20. HES2 and HES3 genes were mapped to human chromosome 1p36.31, while HES5 gene to 1p36.32. HES2 mRNA was expressed in placenta, pancreatic cancer, colon cancer with RER, cervical cancer, and in head and neck tumors. HES5 mRNA was expressed in fetal heart, and brain tumors. Human HES family proteins were found consisting of bHLH, Orange, Proline-rich domains, and WRPW motif. Phylogenetic analyses revealed that HES family proteins were distantly related except a paralog pair of HES1 and HES4. HES family genes are pharmacogenomic targets in the field of regenerative medicine and oncology.

Amino Acid Motifs↗
PubMed1999

Target specificities of Drosophila enhancer of split basic helix-loop-helix proteins.

Seven Enhancer of split genes in Drosophila melanogaster encode basic-helix-loop-helix transcription factors which are components of the Notch signalling pathway. They are expressed in response to Notch activation and mediate some effects of the pathway by regulating the expression of target genes. Here we have determined that the optimal DNA binding site for the Enhancer of split proteins is a palindromic 12-bp sequence, 5'-TGGCACGTG(C/T)(C/T)A-3', which contains an E-box core (CACGTG). This site is recognized by all of the individual Enhancer of split basic helix-loop-helix proteins, consistent with their ability to regulate similar target genes in vivo. We demonstrate that the 3 bp flanking the E-box core are intrinsic to DNA recognition by these proteins and that the Enhancer of split and proneural proteins can compete for binding on specific DNA sequences. Furthermore, the regulation conferred on a reporter gene in Drosophila by three closely related sequences demonstrates that even subtle sequence changes within an E box or flanking bases have dramatic consequences on the overall repertoire of proteins that can bind in vivo.

Animals↗
PubMed2001

A molecular clock involved in somite segmentation.

Somites are transient embryonic structures that are formed from the unsegmented presomitic mesoderm (PSM) in a highly regulated process called somitogenesis. Somite, formation can be considered as the result of several sequential processes: generation of a basic metameric pattern, specification of the antero-posterior identity of each somite, and, finally, formation of the somitic border. Evidence for the existence of a molecular clock or oscillator linked to somitogenesis has been provided by the discovery of the rhythmic and dynamic expression in the PSM of c-hairy1 and lunatic fringe, two genes potentially related to the Notch signaling pathway. These oscillating expression patterns suggest that an important role of the molecular clock could reside in the temporal control of periodic Notch activation, ultimately resulting in the regular array of the somites. We discuss both the importance of the Notch signaling pathway in the molecular events of somitogenesis and its relationship with the molecular clock, and, finally, in that context we review a number of other genes known to play a role in somitogenesis.

Animals↗
PubMed2007

MAPK regulation of maternal and zygotic Notch transcript stability in early development.

Spatiotemporal modulation of the evolutionarily conserved, intercellular Notch signaling pathway is important in the development of many animals. Examples include the regulation of neural-epidermal fate decisions in neurogenic ectoderm of Drosophila and somitogenesis in vertebrate presomitic mesoderm. In both these and most other cases, it appears that Notch-class transmembrane receptors are ubiquitously expressed. Modulation of the pathway is achieved primarily by the localized expression of the activating ligand or by alteration of receptor specificity through a glycosyl transferase. In contrast, we present this report of an instance where the abundance of the Notch-class mRNA itself is dynamically regulated. Taking advantage of the long cell cycle of the two-cell-stage embryo of the leech Helobdella robusta, we show that this regulation is achieved at the levels of both transcript stability and transcription. Moreover, MAPK signaling plays a significant role in regulating accumulation of the transcript by virtue of its effect on Hro-notch mRNA stability. Intracellular injection of heterologous reporter mRNAs shows that the Hro-notch 3' UTR, containing seven AU-rich elements, is key to regulating transcript stability. Thus, we show that regulation of the Notch pathway can occur at a previously underappreciated level, namely that of transcript stability. Given that AU-rich elements occur in the 3' UTR of Notch-class genes in Drosophila, human, and Caenorhabditis elegans, regulation of Notch signaling by modulation of mRNA levels may be operating in other animals as well.

Animals↗
PubMed2003

Constitutive activation of Notch3 inhibits terminal epithelial differentiation in lungs of transgenic mice.

Notch3 is a transmembrane receptor and a member of the Notch signaling pathway essential for cellular differentiation in a variety of developing tissues in both invertebrates and vertebrates. Emerging data support the role of the Notch signaling pathway in tumorigenesis. We have previously demonstrated the expression of Notch3 in a subset of lung adenocarcinomas. To further elucidate the role of Notch3 in development of lung cancer, we established a transgenic mouse model in which the intracellular domain of Notch3 is expressed using the surfactant protein C promoter/enhancer. Constitutive expression of Notch3 in the peripheral epithelium in the developing lung resulted in altered lung morphology and delayed development, leading to perinatal lethality in these transgenic mice. Cell-specific markers and electron microscopy examination showed that the majority of the epithelial cells are undifferentiated, with some maturation of type II pneumocytes. No type I alveolar cells were evident. Metaplasia of undifferentiated cells in the terminal airways was also observed. Although the mice did not live long enough to assess tumor development, these findings demonstrate that ectopic expression of Notch3 in airway epithelium potentially contributes to the multistep evolution of lung cancer through the inhibition of terminal differentiation.

Adenocarcinoma↗
PubMed2006

Notch signaling induces apoptosis in primary human CD34+ hematopoietic progenitor cells.

Notch signaling regulates diverse cell fate decisions during development and is reported to promote murine hematopoietic stem cell (HSC) self-renewal. The purpose of this study was to define the functional consequences of activating the Notch signaling pathway on self-renewal in human HSCs. Subsets of human umbilical cord blood CD34(+) cells were retrovirally transduced with the constitutively active human Notch 1 intracellular domain (N1ICD). N1ICD-transduced cells proliferated to a lesser extent in vitro than cells transduced with vector alone, and this was accompanied by a reduction in the percentage and absolute number of CD34(+) cell populations, including CD34(+)Thy(+)Lin(-) HSCs. Ectopic N1ICD expression inhibited cell cycle kinetics concurrent with an upregulation of p21 mRNA expression and induced apoptosis. Transduction of cells with HES-1, a known transcriptional target of Notch signaling and a mediator of Notch function, had no effect on HSC proliferation, indicating that the mechanism of the Notch-induced effect is HES-1-independent. The results of this study show that activation of the Notch signaling pathway has an inhibitory effect on the proliferation and survival of human hematopoietic CD34(+) cells populations. These findings have important implications for strategies aimed at promoting self-renewal of human HSCs.

Antigens, CD34↗
PubMed1997

The ins and outs of notch signaling.

The Notch gene encodes a cell surface protein that regulates cell fate choices in vertebrates and invertebrates. Given the wide variety of cell types influenced by Notch, it would seem that the signal relayed through Notch activation is not an instructive one per se. Rather, Notch signaling is thought to influence the cell's ability to respond to instructive signals responsible for specific cell fates. Expression and functional studies of Notch support this idea; however, the possibility of additional functions for Notch cannot be excluded. Much of what we know about the Notch signaling pathway comes from studies with Drosophila Notch and the Caenorhabditis elegans Notch-related genes lin-12 and glp-1. With the isolation of multiple vertebrate Notch genes we are beginning to understand and define Notch signaling in vertebrates as well. A number of excellent reviews have been published summarizing the current status of Notch/LIN-12/GLP-1 signaling in Drosophila and C. elegans, as well as recent findings with the vertebrate counterparts. Here I review the structure of the various Notch proteins and their putative ligands, and discuss possible interactions between Notch, its ligands, and other cellular components that affect Notch signal transduction. A role for Notch signaling during normal development and in disease processes is discussed in an accompanying review by T. Gridley (1997, Mol. Cell. Neurosci. 9: 103-108).

Animals↗
PubMed2005

CSL: a notch above the rest.

CSL (CBF1, Suppressor of Hairless, Lag-1) is a transcription factor that is responsible for activating the genes downstream of the Notch signalling pathway, a pathway that is essential for the development of the nervous system and the differentiation of the haematopoietic system among others. In the absence of Notch signalling, CSL represses transcription of Notch target genes, and following activation by Notch, CSL is converted into a transcriptional activator and activates transcription of the same genes. These two opposing functions of CSL are mediated through interactions with distinct protein complexes. The Notch signalling pathway and its crucial cofactor CSL can maintain cells in an undifferentiated state, and have therefore been associated with a growing list of cancers. In addition, CSL has been co-opted by Epstein-Barr virus to mediate viral and host gene transcription following infection.

Amino Acid Sequence↗
PubMed1996

The amino-terminal domains of Epstein-Barr virus nuclear proteins 3A, 3B, and 3C interact with RBPJ(kappa).

The ability of Epstein-Barr virus (EBV) latent infection nuclear protein EBNA3C to activate transcription of two EBNA2-responsive genes and to inhibit EBNA2 activation of transcription in transient-transfection assays appears to be due to its ability to interact with RBPJkappa, a cell protein that links EBNA2 to its response elements. We now show that EBNA3A and EBNA3B expressed in non-EBV-infected Burkitt tumor lymphoblasts are similar to EBNA3C in binding to glutathione S-transferase-RBPJkappa in vitro and in coimmunoprecipitating from cell lysates with antibody to RBPJkappa. EBNA3A and EBNA3B can also inhibit the interaction of RBPJkappa with cognate DNA in vitro. Although EBNA3 open reading frames are each close to 1,000 codons long, EBNA3A amino acids 1 to 138, EBNA3B amino acids 1 to 311, and EBNA3C amino acids 1 to 183 are sufficient for RBPJkappa interaction, while EBNA3B amino acids I to 109 have less or no binding. The RBPJkappa interacting domains overlap with the most highly conserved domain (amino acids 90 to 320) among the EBNA3 proteins. Thus, the EBNA3 gene family appears to have evolved to differentially regulate promoters with RBPJkappa binding sites. EBNA2, EBNA3A, and EBNA3C are important in EBV transformation of primary human B lymphocytes. Their interaction with RBPJkappa links EBV transformation to the notch signaling pathway and the effects of activated notch in T-cell leukemogenesis.

Antigens, Viral↗
PubMed2004

Identification and characterization of human HESL, rat Hesl and rainbow trout hesl genes in silico.

Activation of Notch signaling pathway leads to nuclear translocation of Notch intracellular domain (NIC), and transcriptional activation of target genes through the interaction between CSL proteins (RBPSUH or RBPSUHL) and NIC. HES1, HES5, HEY1 and HEY2 are Notch target genes. Mammalian HES/HEY family proteins as well as Drosophila Hairy and Enhancer of split are implicated in the cell fate determination. We have previously identified and characterized human HES2, HES3 and HES5 genes. Here, we identified and characterized human HES-like (HESL), rat Fesl, and rainbow trout fesl genes by using bioinformatics. Human HESL gene, located within AC093824.3 genome sequence, was mapped to human chromosome 4q35.1 between ACSL1 and SLC25A4 genes. Rat Fesl gene, located within AC111303.4 genome sequence, was mapped to rat chromosome 16q11. EST BX875070.2 was the representative rainbow trout fesl cDNA. HESL-ACSL1 locus was conserved among human, rat, mouse, and zebrafish genomes. Human HESL (241 aa) showed 92.9% total-amino-acid identity with rat Hesl (240 aa), 92.1% total-amino-acid identity with mouse Hesl (240 aa), and 68.0% total-amino-acid identity with rainbow trout hesl (235 aa). HESL orthologs consist of basic Helix-loop-helix (bHLH) domain and ORANGE domain. C-terminal region of HESL orthologs were divergent from that of HES, HEY, and DEC homologs. Phylogenetic analyses revealed that bHLH transcription factors with ORANGE domain were classified into the following three groups: (group I) HES1, HES2, HES4 and HES6 orthologs; (group II) HESL, HES5, HES7, HEY1, HEY2 and HEYL orthologs; (group III) HES3, DEC1/BHLHB2 and DEC2/BHLHB3 orthologs.

Amino Acid Sequence↗
PubMedDate not supplied

Notch3 intracellular domain accumulates in HepG2 cell line.

BACKGROUND: By mediating local cell-cell interactions, the Notch signaling pathway seems to control a variety of processes from cell fate decisions during development, to stem cell renewal and to differentiation in many adult tissues. Hence, perturbed Notch signaling may be involved both in the development and the spread of cancer. The expression and the functional role of some major components of the Notch signaling pathway in human hepatocellular carcinoma (HCC) are poorly characterized. MATERIALS AND METHODS: Notch3, HES1, Jagged1 and Delta1 were analyzed both at the RNA and protein levels in the HepG2 liver cell line derived from human HCC. RESULTS: The results of this study demonstrated, for the first time, that both Jagged1 and Delta1 ligands and the downstream effector gene HES1 are expressed in the HepG2 actively proliferating cell line. Moreover, a high expression of Notch3 intracellular domain, indicative of constitutively activated Notch signaling, was the only detectable Notch3 subunit in HepG2. CONCLUSION: These findings suggest that Notch3 may be involved in mechanisms controling the differentiation and the spread of HCC and that Notch3 activation may be dependent on both Jagged1 and Delta 1 ligands.

Basic Helix-Loop-Helix Proteins↗
PubMed2000

The mouse rib-vertebrae mutation disrupts anterior-posterior somite patterning and genetically interacts with a Delta1 null allele.

Rib-vertebrae (rv) is an autosomal recessive mutation in mouse that affects the morphogenesis of the vertebral column. Axial skeleton defects vary along the anterior-posterior body axis, and include split vertebrae and neural arches, and fusions of adjacent segments. Here, we show that defective somite patterning underlies the vertebral malformations and altered Notch signaling may contribute to the phenotype. Somites in affected regions are irregular in size and shape, epithelial morphology is disrupted, and anterior-posterior somite patterning is abnormal, reminiscent of somite defects obtained in loss-of-function alleles of Notch signaling pathway components. Expression of Dll1, Dll3, Lfng and Notch1 is altered in rv mutant embryos, and rv and Dll1(lacZ), a null allele of the Notch ligand Delta1, genetically interact. Mice double heterozygous for rv and Dll1(lacZ), show vertebral defects, and one copy of Dll1(lacZ) on the homozygous rv background enhances the mutant phenotype and is lethal in the majority of cases. However, fine genetic mapping places rv into an interval on chromosome seven that does not contain a gene encoding a known component of the Notch signaling pathway.

Animals↗
PubMed2003

Functional Notch signaling is required for BMP4-induced inhibition of myogenic differentiation.

The bone morphogenetic protein (BMP) and Notch signaling pathways are crucial for cellular differentiation. In many cases, the two pathways act similarly; for example, to inhibit myogenic differentiation. It is not known whether this inhibition is caused by distinct mechanisms or by an interplay between Notch and BMP signaling. Here we demonstrate that functional Notch signaling is required for BMP4-mediated block of differentiation of muscle stem cells, i.e. satellite cells and the myogenic cell line C2C12. Addition of BMP4 during induction of differentiation dramatically reduced the number of differentiated satellite and C2C12 cells. Differentiation was substantially restored in BMP4-treated cultures by blocking Notch signaling using either the gamma-secretase inhibitor L-685,458 or by introduction of a dominant-negative version of the Notch signal mediator CSL. BMP4 addition to C2C12 cells increased transcription of two immediate Notch responsive genes, Hes1 and Hey1, an effect that was abrogated by L-685,458. A 3 kb Hey1-promoter reporter construct was synergistically activated by the Notch 1 intracellular domain (Notch 1 ICD) and BMP4. The BMP4 mediator SMAD1 mimicked BMP activation of the Hey1 promoter. A synthetic Notch-responsive promoter containing no SMAD1 binding sites responded to SMAD1, indicating that DNA-binding activity of SMAD1 is not required for activation. Accordingly, Notch 1 ICD and SMAD1 interacted in binding experiments in vitro. Thus, the data presented here provide evidence for a direct interaction between the Notch and BMP signaling pathways, and indicate that Notch has a crucial role in the execution of certain aspects of BMP-mediated differentiation control.

Animals↗
PubMed1998

Sanpodo and Notch act in opposition to Numb to distinguish sibling neuron fates in the Drosophila CNS.

In Drosophila, most neuronal siblings have different fates ('A/B'). Here we demonstrate that mutations in sanpodo, a tropomodulin actin-binding protein homologue, equalize a diverse array of sibling neuron fates ('B/B'). Loss of Notch signaling gives the same phenotype, whereas loss of numb gives the opposite phenotype ('A/A'). The identical effect of removing either sanpodo or Notch function on the fates of sibling CNS neurons indicates that sanpodo may act in the Notch signaling pathway. In addition, sanpodo and numb show dosage-sensitive interactions and epistasis experiments indicate that sanpodo acts downstream of numb. Taken together, these results show that interactions between sanpodo, the Notch signaling pathway and numb enable CNS sibling neurons to acquire different fates.

Animals↗
PubMed1999

Decreased amplitude of left ventricular posterior wall motion with notch movement to determine the left posterior septal accessory pathway in Wolff-Parkinson-White syndrome.

OBJECTIVE: To determine preoperatively, by analysing asynchronous left ventricular wall motion, whether to approach through the right ventricle or the left ventricle when carrying out catheter ablation of the accessory pathway in Wolff-Parkinson-White syndrome, especially in patients with the pathway located on the septum. METHODS: 73 patients with manifest Wolff-Parkinson-White syndrome who underwent successful catheter ablation were studied. Location of accessory pathway was classified as right ventricular side: right anterior paraseptum, right anterior, right lateral, right posterior, anterior septum, midseptum, right posterior septum; left ventricular side: left posterior septum, left posterior, left lateral, left anterior. Asynchronous systolic wall motion was analysed by cross sectional echocardiography. RESULTS: Echocardiography showed that the amplitude of left ventricular posterior systolic wall motion was reduced when the pathway was located on the left ventricular side as opposed to the right ventricular side (mean (SD), 11.1 (1.7) v 12.9 (1.1) mm, p < 0.001), especially in patients with left posterior septal accessory pathway (9.7 (0.8) mm). There were no overlapping values between the left posterior septal accessory pathway and the right ventricular side accessory pathway. Posterior wall notch motion was observed in all patients with a left posterior septal accessory pathway (9/9), but not at all in patients with pathways located on the right ventricular side of the septum. In patients with a septal accessory pathway, an ECG algorithm provided poor information (relatively low sensitivity, specificity, and predictive value) for determining whether the subsite faced either the left (left posterior septum) or the right ventricle (anterior septum, midseptum, right posterior septum). CONCLUSIONS: Decreased amplitude of left ventricular posterior wall motion with notch movement is an important finding for accessory pathways located on the left posterior septum. These findings provided clinically useful information for determining whether to approach catheter ablation from the right or the left ventricle.

Adolescent↗
PubMed2003

Interaction of the MAGUK family member Acvrinp1 and the cytoplasmic domain of the Notch ligand Delta1.

The evolutionarily conserved Notch signal transduction pathway regulates cell fate and cellular differentiation in various tissues and has essential functions in embryonic patterning and tumorigenesis. Cell-cell signaling by the Notch pathway is mediated by the interaction of the transmembrane receptor Notch with its ligands Delta or Jagged presented on adjacent cells. Whereas signal transduction to Notch expressing cells has been described, it is unclear whether Delta-dependent signaling may exist within the Delta-expressing cell. Here, we report on the identification of Acvrinp1, a MAGUK family member, interacting with the intracellular domain of Delta1 (Dll1). We confirmed the interaction between Dll1 and Acvrinp1 by pull-down experiments in vitro and in a mammalian two-hybrid system in vivo. We delimited the fourth PDZ domain of Acvrinp1 and the PDZ-binding domain of Dll1 as major interacting domains. In situ expression analyses in mouse embryos revealed that Dll1 and Acvrinp1 show partly overlapping but distinct expression patterns, for example, in the central nervous system and the vibrissae buds. Further, we found that expression of Acvrinp1 is altered in Dll1 loss-of-function mouse embryos.

Activin Receptors, Type II↗
PubMed2004

Notch signaling in vascular morphogenesis.

PURPOSE OF REVIEW: This review highlights recent developments in the role of the Notch signaling pathway during vascular morphogenesis, angiogenesis, and vessel homeostasis. RECENT FINDINGS: Studies conducted over the past 4 years have significantly advanced the understanding of the effect of Notch signaling on vascular development. Major breakthroughs have elucidated the role of Notch in arterial versus venular specification and have placed this pathway downstream of vascular endothelial growth factor. SUMMARY: An emerging hallmark of the Notch signaling pathway is its nearly ubiquitous participation in cell fate decisions that affect several tissues, including epithelial, neuronal, hematopoietic, and muscle. The vascular compartment has been the latest addition to the list of tissues known to be regulated by Notch. Unraveling the contribution of Notch signaling to blood vessel formation has resulted principally from gain-of-function and loss-of-function experiments in mouse and zebrafish. During the past 4 years, these mechanistic studies have revealed that Notch is required for the successful completion of several steps during vascular morphogenesis and differentiation. In addition, the findings that Notch mutations are linked to some late-onset hereditary vascular pathologic conditions suggest the added contribution of this signaling pathway to vascular homeostasis.

Animals↗