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PubMed2001

Presenilin mutations and calcium signaling defects in the nervous and immune systems.

Presenilin-1 (PS1) is thought to regulate cell differentiation and survival by modulating the Notch signaling pathway. Mutations in PS1 have been shown to cause early-onset inherited forms of Alzheimer's disease (AD) by a gain-of-function mechanism that alters proteolytic processing of the amyloid precursor protein (APP) resulting in increased production of neurotoxic forms of amyloid beta-peptide. The present article considers a second pathogenic mode of action of PS1 mutations, a defect in cellular calcium signaling characterized by overfilling of endoplasmic reticulum (ER) calcium stores and altered capacitive calcium entry; this abnormality may impair synaptic plasticity and sensitize neurons to apoptosis and excitotoxicity. The calcium signaling defect has also been documented in lymphocytes, suggesting a contribution of immune dysfunction to the pathogenesis of AD. A better understanding of the calcium signaling defect resulting from PS1 mutations may lead to the development of novel preventative and therapeutic strategies for disorders of the nervous and immune systems.

Alzheimer Disease↗
PubMed2003

Characterization of Notch3-deficient mice: normal embryonic development and absence of genetic interactions with a Notch1 mutation.

The Notch signaling pathway is an evolutionarily conserved signaling mechanism and mutations in its components disrupt cell fate specification and embryonic development in many organisms. To analyze the in vivo role of the Notch3 gene in mice, we created a deletion allele by gene targeting. Embryos homozygous for this mutation developed normally and homozygous mutant adults were viable and fertile. We also examined whether we could detect genetic interactions during early embryogenesis between the Notch3 mutation and a targeted mutation of the Notch1 gene. Double homozygous mutant embryos exhibited defects normally observed in Notch1-deficient embryos, but we detected no obvious synergistic effects in the double mutants. These data demonstrate that the Notch3 gene is not essential for embryonic development or fertility in mice, and does not have a redundant function with the Notch1 gene during early embryogenesis.

Animals↗
PubMed2003

Lytic but not latent infection by Kaposi's sarcoma-associated herpesvirus requires host CSL protein, the mediator of Notch signaling.

Infection by Kaposi's sarcoma (KS)-associated herpesvirus (KSHV) is a key factor in the development of KS. Both latent and lytic KSHV infection is observed in KS tumor cells, and both genetic programs contribute importantly to KS pathogenesis. The viral replication and transcription activator (RTA) protein is a transcription factor that controls the switch from latency to lytic replication. We have previously shown that RTA can activate the expression of several lytic viral genes in transfected cells by interaction with recombination signal sequence-binding protein-J kappa (RBP-J kappa, also called CSL), which in uninfected cells is a transcriptional repressor that is the target of the Notch-signaling pathway. The recognition that many KSHV lytic genes, including RTA itself, contain RBP-J kappa-binding sites raised the possibility that RBP-J kappa-mediated repression may be central to the establishment of latency. Here, we have tested this hypothesis by examining KSHV infection of RBP-J kappa-null murine fibroblasts. Our results show that KSHV latency is efficiently induced in such cells; however, the reactivation of lytic gene expression, viral DNA replication, and the release of progeny viruses are dramatically inhibited in the absence of RBP-J kappa. RBP-J kappa-mediated repression is therefore not essential for establishment of latent infection, but the RTA-mediated redirection of RBP-J kappa activity from repression to activation is critical for lytic viral replication.

Animals↗
PubMed2001

A functional composite cis-element for NF kappa b and RBJ kappa in the rat pregnancy-specific glycoprotein gene.

The rat pregnancy-specific glycoprotein gene rnCGM3 is primarily expressed in the placenta. Previously, three DNase I footprinting sites (FPI, FPII, and FPIII) were identified in the rnCGM3 promoter region, a yeast one-hybrid screen was performed to identify the nuclear factors binding to the FPIII (5'-GCCTGGGAAAAAACTC-3') element, and RBPJ kappa, a downstream effector of the Notch signaling pathway, was identified as one of the FPIII-binding factors. In the present study, the NF kappa B member p65 was identified as another FPIII-binding factor. Electrophoretic mobility shift assays showed that NF kappa B members, including p50 and p65, bound to the FPIII site. The core binding sequence in the FPIII element for p50 and p65 is GGGAAA, which overlaps with that for RBPJ kappa. Competition exists between p50 and RBPJ kappa for binding to the FPIII element. Transient expression analyses revealed that p65 significantly stimulated the expression of a reporter gene directed by the NF kappa B core sequence in the FPIII element. However, RBPJ kappa could block this stimulation. These results suggest that the regulation of rnCGM3 expression involves both NF kappa B and RBPJ kappa, and they are mutually exclusive in the FPIII element.

Animals↗
PubMed2007

Glucocorticoid and growth factor synergism requirement for Notch4 chromatin domain activation.

The Notch signaling pathway modulates cell fate in diverse contexts, including vascular development. Notch4 is selectively expressed in vascular endothelium and regulates vascular remodeling. The signal-dependent transcription factor activator protein 1 (AP-1) activates Notch4 transcription in endothelial cells, but other factors/signals that regulate Notch4 are largely unknown. We demonstrate that, unlike the established transrepression mechanism in which the glucocorticoid receptor (GR) antagonizes AP-1, AP-1 and GR synergistically activated Notch4 transcription in endothelial cells. Fibroblast growth factor 2 (FGF-2) and cortisol induced AP-1 and GR occupancy, respectively, at a Notch4 promoter composite response element consisting of an imperfect half-glucocorticoid response element and an AP-1 motif, which mediated signal-dependent activation. Analysis of Notch4 promoter complex assembly provided evidence that GR and AP-1 independently occupy the composite response element, but AP-1 stabilizes GR occupancy. In multipotent 10T1/2 cells, FGF-2 and cortisol induced a histone modification pattern at the Notch4 locus mimicking that present in endothelial cells and reprogrammed Notch4 from a repressed to an active state. These results establish the molecular basis for a novel AP-1/GR-Notch4 axis in vascular endothelium.

Animals↗
PubMed2005

The Enhancer of split and Achaete-Scute complexes of Drosophilids derived from simple ur-complexes preserved in mosquito and honeybee.

BACKGROUND: In Drosophila melanogaster the Enhancer of split-Complex [E(spl)-C] consists of seven highly related genes encoding basic helix-loop-helix (bHLH) repressors and intermingled, four genes that belong to the Bearded (Brd) family. Both gene classes are targets of the Notch signalling pathway. The Achaete-Scute-Complex [AS-C] comprises four genes encoding bHLH activators. The question arose how these complexes evolved with regard to gene number in the evolution of insects concentrating on Diptera and the Hymenoptera Apis mellifera. RESULTS: In Drosophilids both gene complexes are highly conserved, spanning roughly 40 million years of evolution. However, in species more diverged like Anopheles or Apis we find dramatic differences. Here, the E(spl)-C consists of one bHLH (mbeta) and one Brd family member (malpha) in a head to head arrangement. Interestingly in Apis but not in Anopheles, there are two more E(spl) bHLH like genes within 250 kb, which may reflect duplication events in the honeybee that occurred independently of that in Diptera. The AS-C may have arisen from a single sc/l'sc like gene which is well conserved in Apis and Anopheles and a second ase like gene that is highly diverged, however, located within 50 kb. CONCLUSION: E(spl)-C and AS-C presumably evolved by gene duplication to the nowadays complex composition in Drosophilids in order to govern the accurate expression patterns typical for these highly evolved insects. The ancestral ur-complexes, however, consisted most likely of just two genes: E(spl)-C contains one bHLH member of mbeta type and one Brd family member of malpha type and AS-C contains one sc/l'sc and a highly diverged ase like gene.

Amino Acid Sequence↗
PubMed1999

Hes1 and Hes5 as notch effectors in mammalian neuronal differentiation.

While the transmembrane protein Notch plays an important role in various aspects of development, and diseases including tumors and neurological disorders, the intracellular pathway of mammalian Notch remains very elusive. To understand the intracellular pathway of mammalian Notch, the role of the bHLH genes Hes1 and Hes5 (mammalian hairy and Enhancer-of-split homologues) was examined by retrovirally misexpressing the constitutively active form of Notch (caNotch) in neural precursor cells prepared from wild-type, Hes1-null, Hes5-null and Hes1-Hes5 double-null mouse embryos. We found that caNotch, which induced the endogenous Hes1 and Hes5 expression, inhibited neuronal differentiation in the wild-type, Hes1-null and Hes5-null background, but not in the Hes1-Hes5 double-null background. These results demonstrate that Hes1 and Hes5 are essential Notch effectors in regulation of mammalian neuronal differentiation.

Animals↗
PubMed1997

Grg3, a murine Groucho-related gene, is expressed in the developing nervous system and in mesenchyme-induced epithelial structures.

We have isolated cDNAs representing multiple members of murine groucho homologues, designated Grg for groucho-related genes. Among them, Grg3 appears to produce two transcripts. One of the Grg3 transcripts contains coding sequence for a complete Groucho protein homologue. The second transcript contains coding sequence for only the two amino-terminal domains of the Groucho protein, followed by a hydrophobic tail and a stop codon. We analyzed the expression of both transcripts in mouse embryos using RNase protection and in situ hybridization. Expression was detected during cell determination in the nervous system and in somitic mesoderm, overlapping Notch1 expression and adjacent to Mash1, MyoD and Myf5 expression. Thus, the expression pattern of Grg3 suggests a conserved role in the Notch signalling pathway to regulate expression of basic helix-loop-helix proteins and cell determination. Grg3 expression was also consistently detected in epithelial structures undergoing mesenchyme induction.

Alternative Splicing↗
PubMed2000

Sensory organ generation in the chicken inner ear: contributions of bone morphogenetic protein 4, serrate1, and lunatic fringe.

The chicken inner ear is a remarkably complex structure consisting of eight morphologically distinct sensory organs. Unraveling how these sensory organs are specified during development is key to understanding how such a complex structure is generated. Previously, we have shown that each sensory organ in the chicken inner ear arises independently in the rudimentary otocyst based on Bone morphogenetic protein 4 (Bmp4) expression. Here, we compare the expression of Bmp4 with two other putative sensory organ markers, Lunatic Fringe (L-fng) and chicken Serrate1 (Ser1), both of which are components of the Notch signaling pathway. L-fng and Ser1 expression domains were asymmetrically distributed in the otic cup. At this early stage, expression of L-fng is similar to Delta1 (Dl1), in an anteroventral domain apparently corresponding to the neurogenic region, while Ser1 is expressed at both the anterior and posterior poles. By the otocyst stage, the expression of both L-fng and Ser1 largely coincided in the medial region. All presumptive sensory organs, as identified by Bmp4 expression, arose within the broad L-fng- and Ser1-positive domain, indicating the existence of a sensory-competent region in the rudimentary otocyst. In addition, there is a qualitative difference in the levels of expression between L-fng and Ser1 such that L-fng expression was stronger in the ventral anterior, whereas Ser1 was stronger in the dorsal posterior region of this broad domain. This early difference in expression may presage the differences among sensory organs as they arise from this sensory competent zone.

Age Factors↗
PubMed2001

Mutation analysis of Jagged1 (JAG1) in Alagille syndrome patients.

Alagille syndrome (AGS) is an autosomal dominant disorder caused by mutations in Jagged1 (JAG1), a ligand in the evolutionarily conserved Notch signaling pathway. Previous studies have demonstrated that a wide spectrum of JAG1 mutations result in AGS. These include total gene deletions, protein truncating, splicing and missense mutations which are distributed across the coding region of the gene. Here we present results of JAG1 mutation screening by SSCP and FISH in 105 patients with AGS. For these studies, new primers were designed for 12 exons. Mutations were identified in 63/105 patients (60%). The spectrum of the JAG1 mutations presented here is consistent with previously reported results. Eighty three percent (52/63) of the mutations were protein truncating, 11% (7/63) were missense, 2% (1/63) were splice site, and 5% (3/63) were total gene deletions demonstrable by FISH. Six of the missense mutations are novel. As has been reported previously, there is no apparent relationship between genotype and clinical phenotype.

Alagille Syndrome↗
PubMed2002

Craniosynostosis in Alagille syndrome.

Alagille syndrome is a multisystem developmental disorder with primary involvement of the liver, heart, skeleton, eyes and facial structures, and demonstrates highly variable expressivity with respect to all of the involved systems. Alagille syndrome is caused by mutations in the Jagged1 gene. Jagged1 is a ligand in the Notch signaling pathway that has been shown to regulate early cell fate determination. Mutations in Jagged1 have been identified in approximately 80% of patients with Alagille syndrome. We have recently identified two patients with mutation proven Alagille syndrome who also had unilateral coronal craniosynostosis. Both individuals were screened for mutations in fibroblast growth factor receptor 1, 2, 3 and TWIST genes, all associated with various types of craniosynostosis and no mutations were identified. The finding of a conserved form of craniosynostosis in two unrelated patients with Alagille syndrome and mutations in Jagged1 may indicate that Jagged1 plays a role in cranial suture formation.

Alagille Syndrome↗
PubMed2004

Hepatic fibrosis in Kabuki syndrome.

Kabuki (Niikawa-Kuroki) syndrome (KS) is characterized by a distinctive face, mental retardation, growth deficiency, skeletal anomalies, dermatoglyphic abnormalities, palatal anomalies, congenital heart defects, and urogenital malformations. Congenital hepatic abnormalities have been sporadically described in patients with KS from the literature, consisting of extrahepatic biliary atresia, neonatal sclerosing cholangitis, and severe neonatal jaundice. We report here on an additional patient with a congenital abnormality of the liver consisting of hepatic fibrosis. To our knowledge, idiopathic congenital hepatic fibrosis has not been reported in KS. Thus, our observation expands the spectrum of liver malformations found in KS with the inclusion of hepatic fibrosis and supports the evidence that hepatic abnormalities may not be uncommon in KS. Clinician should be advised to search for the specific facial anomalies of KS in patients with syndromic congenital hepatic diseases, and KS should be added to the list of previously recognized multiple congenital anomaly syndromes with hepatic involvement. Due to the frequent association with congenital heart malformations, KS should be considered in the evaluation of patients with neonatal liver disease and cardiac malformation. Due to the expression patterns of Notch genes, involvement of the Notch signaling pathway in the development of heart and liver anomalies in KS should be considered.

Abnormalities, Multiple↗
PubMed2006

DLL3 as a candidate gene for vertebral malformations.

Investigations have not identified a major locus for congenital vertebral malformations. Based on observations in mice, we hypothesized that mutations in DLL3, a member of the notch-signaling pathway, might contribute to human vertebral malformations. We sequenced the DLL3 gene in 50 patients with congenital vertebral malformations. A Caucasian male patient with VACTERL manifestations including a T5-T6 block vertebrae was heterozygous for a "G" to "A" missense mutation changing glycine to arginine at codon 269. This residue is conserved in mammals, including chimpanzee, mouse, dog, and rat. Additional testing in the patient did not show evidence of chromosome abnormalities. The patient's asymptomatic mother was also heterozygous for the missense mutation. Since this mutation was not observed in a control population and leads to an amino acid change, it may be clinically significant. The mutation was not found in a control population of 87 anonymous individuals. Several established mechanisms could explain the mutation in both the patient and his asymptomatic mother (susceptibility allele requiring additional environmental factors, somatic mosaicism, multigenic inheritance). Documenting the absence of the mutation in a larger control population or the presence of the mutation in additional affected patients, or documenting a functional difference in DLL3 would provide further evidence supporting its causal role.

Adult↗
PubMedDate not supplied

No evidence for SEL1L as a candidate gene for IDDM11-conferred susceptibility.

BACKGROUND: The SEL1L gene is located on human chromosome 14q24.3-31 close to D14S67 which has been previously proposed to be a type 1 diabetes mellitus locus (IDDM11). Sel-1 is a negative regulator of the Notch signalling pathway and SEL1L is selectively expressed in adult pancreas and islets of Langerhans. This suggests that SEL1L may be a candidate gene for IDDM11. METHODS: We have analysed two newly identified CA-repeat polymorphisms within the genomic sequence of the SEL1L locus for association with type 1 diabetes mellitus (T1DM) in 152 Danish T1DM-affected sib-pair families and in 240 Sardinian families (229 simplex and 11 sib-pair families). RESULTS: No evidence for association of the two SEL1L markers with T1DM was observed in either the Danish or the Sardinian families. We have also used allelic sharing methods to analyse linkage with T1DM in the IDDM11 region using the same markers and the Danish collection of affected sib-pair families. No evidence of linkage was observed (Z(max)=0.86). CONCLUSION: Although several lines of evidence suggest that SEL1L might be a candidate for IDDM11-conferred susceptibility to T1DM the present study does not support this hypothesis.

Alleles↗
PubMed2005

Photoreceptor differentiation in Drosophila: from immature neurons to functional photoreceptors.

How a pool of equipotent cells acquires a multitude of distinct fates is a major question in developmental biology. The study of photoreceptor (PR) cell differentiation in Drosophila has been used to address this question. PR differentiation is a process that extends over a period of 5 days: It begins in the larval eye imaginal disc when PRs are recruited and commit to particular PR fates, and it culminates in the pupal eye disc with the morphogenesis of the rhabdomeres and the initiation of rhodopsin expression. Several models for PR specification agree that the Ras and Notch signaling pathways are important for the specification of different PR subtypes (Freeman [1997] Development 124:261-270; Cooper and Bray [2000] Curr. Biol. 10:1507-1510; Tomlinson and Struhl [2001] Mol. Cell. 7:487-495). In the first part of this review, we briefly describe the different signaling pathways and transcription factors required for the specification and differentiation of the different PR subtypes in the larval eye disc. In the second part, we review the roles of several transcription factors, which are required for the terminal photoreceptor differentiation and rhodopsin expression.

Animals↗
PubMed2006

Follicular B helper T cell activity is confined to CXCR5(hi)ICOS(hi) CD4 T cells and is independent of CD57 expression.

The generation of high-affinity antibody-secreting plasma cells critically depends on the presence of CD4 T cells during the germinal center (GC) reaction. GC T cells are so far incompletely characterized in terms of phenotype and function. Here, we show that human follicular B helper T (T(FH)) cells are characterized by high expression of the homeostatic chemokine receptor CXCR5 and the costimulatory molecule ICOS, but not CD57 expression. CXCR5(hi)ICOS(hi) CD4 T cells are the most potent inducers of IgG production that also secrete large amounts of the B cell-attracting chemokine CXCL13. CXCR5(hi)ICOS(hi) CD4 T cells differ from other tonsillar CD4 T cell subsets in their stimulatory activity, proliferative capacity and susceptibility to apoptosis. Large-scale gene expression analysis revealed that T(FH) cells are only distantly related to CXCR5(-) and CXCR5(+) central memory T (T(CM)) as well as effector memory T (T(EM)) cells present in the periphery. CXCR5(hi)ICOS(hi) CD4 T cells appear to be terminally differentiated T helper cells that express a unique set of transcription factors related to the Notch signaling pathway and thus differentiate independent of other T helper cell populations.

Antigens, Differentiation, T-Lymphocyte↗
PubMed2004

Neurogenic phenotypes induced by RNA interference with bHLH genes of the Enhancer of split complex of Drosophila melanogaster.

The Enhancer of split gene complex [E(spl)-C] of Drosophila melanogaster harbors seven highly related genes encoding transcriptional regulators with a basic helix-loop-helix (bHLH) domain. They are activated by the Notch signaling pathway in order to inhibit proneural gene activity, for example, during neurogenesis in the developing embryo. The E(spl) proteins are at least partly redundant, despite some remarkable differences in their expression patterns. We attempted to address the degree of redundancy by means of RNA interference. We find a quantitative correlation between the degree of a neurogenic phenotype and the number of genes affected. Surprisingly, interference with m3 results in a high rate of mortality which cannot be reproduced by genetic mutation. Most likely, m3 dsRNA interferes with unrelated genes involved in other aspects of embryonic development.

Animals↗
PubMed2002

Human cortical glial tumors contain neural stem-like cells expressing astroglial and neuronal markers in vitro.

Neural stem cells from neurogenic regions of mammalian CNS are clonogenic in an in vitro culture system exploiting serum and anchorage withdrawal in medium supplemented with methyl cellulose and the pleiotropic growth factors EGF, FGF2, and insulin. The aim of this study was to test whether cortical glial tumors contain stem-like cells capable, under this culture system, of forming clones showing intraclonal heterogeneity in the expression of neural lineage-specific proteins. The high frequencies of clone-forming cells (about 0.1-10 x 10(-3)) in clinical tumor specimens with mutated p53, and in neurogenic regions of normal human CNS, suggest that the ability to form clones in this culture system is induced epigenetically. RT-PCR analyses of populations of normal brain- and tumor-derived sister clones revealed transcripts for nestin, neuron-specific enolase, and glial fibrillary acidic protein (GFAP). However, the tumor-derived clones were different from clones derived from neurogenic regions of normal brain in the expression of transcripts specific for genes associated with neural cell fate determination via the Notch-signaling pathway (Delta and Jagged), and cell survival at G2 or mitotic phases (Survivin). Moreover, the individual glioma-derived clones contain cells immunopositive separately for GFAP or neuronal beta-III tubulin, as well as single cells coexpressing both glial and neuronal markers. The data suggest that the latent critical stem cell characteristics can be epigenetically induced by growth conditions not only in cells from neurogenic regions of normal CNS but also in cells from cortical glial tumors. Moreover, tumor stem-like cells with genetically defective responses to epigenetic stimuli may contribute to gliomagenesis and the developmental pathological heterogeneity of glial tumors.

Astrocytes↗