Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Notch pathway”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 1,135 records · Page 63Linked to original sources
PubMed2006

Transcriptome and phenotypic analysis reveals Gata3-dependent signalling pathways in murine hair follicles.

The transcription factor Gata3 is crucially involved in epidermis and hair follicle differentiation. Yet, little is known about how Gata3 co-ordinates stem cell lineage determination in skin, what pathways are involved and how Gata3 differentially regulates distinct cell populations within the hair follicle. Here, we describe a conditional Gata3-/- mouse (K14-Gata3-/-) in which Gata3 is specifically deleted in epidermis and hair follicles. K14-Gata3-/- mice show aberrant postnatal growth and development, delayed hair growth and maintenance, abnormal hair follicle organization and irregular pigmentation. After the first hair cycle, the germinative layer surrounding the dermal papilla was not restored; instead, proliferation was pronounced in basal epidermal cells. Transcriptome analysis of laser-dissected K14-Gata3-/- hair follicles revealed mitosis, epithelial differentiation and the Notch, Wnt and BMP signaling pathways to be significantly overrepresented. Elucidation of these pathways at the RNA and protein levels and physiologic endpoints suggests that Gata3 integrates diverse signaling networks to regulate the balance between hair follicle and epidermal cell fates.

Animals↗
PubMed2001

Wasp, the Drosophila Wiskott-Aldrich syndrome gene homologue, is required for cell fate decisions mediated by Notch signaling.

Wiskott-Aldrich syndrome proteins, encoded by the Wiskott-Aldrich syndrome gene family, bridge signal transduction pathways and the microfilament-based cytoskeleton. Mutations in the Drosophila homologue, Wasp (Wsp), reveal an essential requirement for this gene in implementation of cell fate decisions during adult and embryonic sensory organ development. Phenotypic analysis of Wsp mutant animals demonstrates a bias towards neuronal differentiation, at the expense of other cell types, resulting from improper execution of the program of asymmetric cell divisions which underlie sensory organ development. Generation of two similar daughter cells after division of the sensory organ precursor cell constitutes a prominent defect in the Wsp sensory organ lineage. The asymmetric segregation of key elements such as Numb is unaffected during this division, despite the misassignment of cell fates. The requirement for Wsp extends to additional cell fate decisions in lineages of the embryonic central nervous system and mesoderm. The nature of the Wsp mutant phenotypes, coupled with genetic interaction studies, identifies an essential role for Wsp in lineage decisions mediated by the Notch signaling pathway.

Alleles↗
PubMed2000

Neoplastic transformation by Notch is independent of transcriptional activation by RBP-J signalling.

Signalling through the transmembrane receptor Notch is triggered by ligand binding, which induces the proteolytic cleavage of the Notch protein. This cleavage generates an intracellular fragment of the Notch protein (Notch-IC), which translocates into the nucleus and modifies transcription of target genes through its association with the RBP-J protein. Thus, the isolated Notch-IC protein represents the constitutively activated receptor. We have performed a deletion analysis of Notch IC in order to identify the transferable transactivation domain of Notch-IC and the minimal domain of Notch-IC required for RBP-J dependent transactivational activation. Functionally, Notch-IC has been linked to cell fate decision in development and oncogenesis in vivo. In vitro, Notch-IC can cooperate in neoplastic transformation of baby rat kidney cells with the adenoviral E1A protein. We have defined the minimal domain of Notch-IC required for E1A cotransformation. This domain, consisting of the ankyrin repeats of Notch-IC only, can neither activate RBP-J dependent transcription nor does it carry a transactivation domain. Therefore, the ankyrin repeat domain of Notch-IC might trigger novel pathways relevant for transformation but unrelated to RBP-J signalling.

Adenovirus E1A Proteins↗
PubMed2004

Notch function in the vasculature: insights from zebrafish, mouse and man.

Vascular development entails multiple cell-fate decisions to specify a diverse array of vascular structures. Notch proteins are signaling receptors that regulate cell-fate determination in a variety of cell types. The finding that Notch genes are robustly expressed in the vasculature suggests roles for Notch in guiding endothelial and associated mural cells through the myriad of cell-fate decisions needed to form the vasculature. In fact, mice with defects in genes encoding Notch, Notch ligands, and components of the Notch signaling cascade invariably display vascular defects. Human Notch genes are linked to Alagille's Syndrome, a developmental disorder with vascular defects, and CADASIL, a cerebral arteriopathy. Studies in zebrafish, mice and humans indicate that Notch works in conjunction with other angiogenic pathways to pattern and stabilize the vasculature. Here, we will focus on established functions for Notch in vascular remodeling and arterial/venous specification and more speculative roles in vascular homeostasis and organ-specific angiogenesis.

Animals↗
PubMed2004

Notch subunit heterodimerization and prevention of ligand-independent proteolytic activation depend, respectively, on a novel domain and the LNR repeats.

Notch proteins are transmembrane receptors that participate in a highly conserved signaling pathway that regulates morphogenesis in metazoans. Newly synthesized Notch receptors are proteolytically cleaved during transit to the cell surface, creating heterodimeric mature receptors comprising noncovalently associated extracellular (N(EC)) and transmembrane (N) subunits. Ligand binding activates Notch by inducing two successive proteolytic cleavages, catalyzed by metalloproteases and gamma-secretase, respectively, that permit the intracellular portion of N to translocate to the nucleus and activate transcription of target genes. Prior work has shown that the presence of N(EC) prevents ligand-independent activation of N, but the mechanisms involved are poorly understood. Here, we define the roles of two regions at the C-terminal end of N(EC) that participate in maintaining the integrity of resting Notch receptors through distinct mechanisms. The first region, a hydrophobic, previously uncharacterized portion of N(EC), is sufficient to form stable complexes with the extracellular portion of N. The second region, consisting of the three Lin12/Notch repeats, is not needed for heterodimerization but acts to protect N from ligand-independent cleavage by metalloproteases. Together, these two contiguous regions of N(EC) impose crucial restraints that prevent premature Notch receptor activation.

Amino Acid Motifs↗
PubMed2001

Activated Notch2 signaling inhibits differentiation of cerebellar granule neuron precursors by maintaining proliferation.

In the developing cerebellar cortex, granule neuron precursors (GNPs) proliferate and commence differentiation in a superficial zone, the external granule layer (EGL). The molecular basis of the transition from proliferating precursors to immature differentiating neurons remains unknown. Notch signaling is an evolutionarily conserved pathway regulating the differentiation of precursor cells of many lineages. Notch2 is specifically expressed in proliferating GNPs in the EGL. Treatment of GNPs with soluble Notch ligand Jagged1, or overexpression of activated Notch2 or its downstream target HES1, maintains precursor proliferation. The addition of GNP mitogens Jagged1 or Sonic Hedgehog (Shh) upregulates the expression of HES1, suggesting a role for HES1 in maintaining precursor proliferation.

Animals↗
PubMed2001

Notch1IC partially replaces EBNA2 function in B cells immortalized by Epstein-Barr virus.

Immortalization of B cells by Epstein-Barr virus (EBV) depends on the virally encoded EBNA2 protein. Although not related by sequence, the cellular Notch protein and EBNA2 share several biochemical and functional properties, such as interaction with CBF1 and the ability to activate transcription of a number of cellular and viral genes. Whether these similarities are coincidental or exemplify EBNA2 mimicry of evolutionarily conserved cellular signaling pathways is unclear. We therefore investigated whether activated forms of Notch could substitute for EBNA2 in maintaining the immortalized phenotype of EBV-infected B cells. To address this question, we devised a transcomplementation system using EREB2.5 cells. EREB2.5 cells are immortalized by EBV expressing a conditional estrogen receptor EBNA2 fusion protein (EREBNA2), and cellular proliferation is dependent on the availability of estrogen. Withdrawal of estrogen results in inactivation of EREBNA2, leading to growth arrest and eventually to cell death. Transduction of EREB2.5 cells with a lentiviral vector expressing wild-type EBNA2 rescued EREB2.5 cells from the growth-inhibitory effects of estrogen deprivation, in contrast to transduction with the lentivirus vector alone. EREB2.5 cells were also rescued by enforced expression of human Notch1IC after estrogen starvation, but this effect was restricted to cells expressing high levels of the transcription factor. Compared to wild-type EBNA2-expressing EREB2.5 cells, the Notch-expressing cells expanded more slowly after estrogen starvation, and once established, they continued to display a lower proliferation rate. Analysis of viral and cellular gene expression from transduced EREB2.5 cells after estrogen withdrawal indicated that both wild-type EBNA2- and Notch1IC-positive cells expressed c-Myc at levels similar to those found in parental EREB2.5 cells. However, the latter cells expressed LMP-1 far less efficiently than cells transduced with the wild-type EBNA2 gene. Cells rescued by either wild-type EBNA2 or Notch1IC expressed surface CD21 and CD23 proteins, but not CD10, indicating that induction of relevant type III latency markers was maintained. The data imply that both Notch and EBNA2 activate an important subset of cellular genes associated with type III latency and B-cell growth, while EBNA2 more efficiently induces important viral genes, such as LMP-1. Thus, exploitation of conserved Notch-related signaling pathways may represent a key mechanism by which EBNA2 contributes to EBV-induced cell immortalization.

B-Lymphocytes↗
PubMed2006

Independent roles of Drosophila Moesin in imaginal disc morphogenesis and hedgehog signalling.

The three ERM proteins (Ezrin, Radixin and Moesin) form a conserved family required in many developmental processes involving regulation of the cytoskeleton. In general, the molecular function of ERM proteins is to link specific membrane proteins to the actin cytoskeleton. In Drosophila, loss of moesin (moe) activity causes incorrect localisation of maternal determinants during oogenesis, failures in rhabdomere differentiation in the eye and alterations of epithelial integrity in the wing imaginal disc. Some aspects of Drosophila Moe are related to the activity of the small GTPase RhoA, because the reduction of RhoA activity corrects many phenotypes of moe mutant embryos and imaginal discs. We have analysed the phenotype of moesin loss-of-function alleles in the wing disc and adult wing, and studied the effects of reduced Moesin activity on signalling mediated by the Notch, Decapentaplegic, Wingless and Hedgehog pathways. We found that reductions in Moesin levels in the wing disc cause the formation of wing-tissue vesicles and large thickenings of the vein L3, corresponding to breakdowns of epithelial continuity in the wing base and modifications of Hedgehog signalling in the wing blade, respectively. We did not observe any effect on signalling pathways other than Hedgehog, indicating that the moe defects in epithelial integrity have not generalised effects on cell signalling. The effects of moe mutants on Hedgehog signalling depend on the correct gene-dose of rhoA, suggesting that the requirements for Moesin in disc morphogenesis and Hh signalling in the wing disc are mediated by its regulation of RhoA activity. The mechanism linking Moesin activity with RhoA function and Hedgehog signalling remains to be elucidated.

Animals↗
PubMed2001

The tissue polarity gene nemo carries out multiple roles in patterning during Drosophila development.

Drosophila nemo was first identified as a gene required for tissue polarity during ommatidial development. We have extended the analysis of nemo and found that it participates in multiple developmental processes. It is required during wing development for wing shape and vein patterning. We observe genetic interactions between nemo and mutations in the Notch, Wingless, Frizzled and Decapentaplegic pathways. Our data support the findings from other organisms that Nemo proteins act as negative regulators of Wingless signaling. nemo mutations cause polarity defects in the adult wing and overexpression of nemo leads to abdominal polarity defects. The expression of nemo during embryogenesis is dynamic and dsRNA inhibition and ectopic expression studies indicate that nemo is essential during embryogenesis.

Alleles↗
PubMed2005

Hey1, a mediator of notch signaling, is an androgen receptor corepressor.

Hey1 is a member of the basic helix-loop-helix-Orange family of transcriptional repressors that mediate Notch signaling. Here we show that transcription from androgen-dependent target genes is inhibited by Hey1 and that expression of a constitutively active form of Notch is capable of repressing transactivation by the endogenous androgen receptor (AR). Our results indicate that Hey1 functions as a corepressor for AF1 in the AR, providing a mechanism for cross talk between Notch and androgen-signaling pathways. Hey1 colocalizes with AR in the epithelia of patients with benign prostatic hyperplasia, where it is found in both the cytoplasm and the nucleus. In marked contrast, we demonstrate that Hey1 is excluded from the nucleus in most human prostate cancers, raising the possibility that an abnormal Hey1 subcellular distribution may have a role in the aberrant hormonal responses observed in prostate cancer.

Animals↗
PubMed2006

Wnt signalling in lung development and diseases.

There are several signalling pathways involved in lung organogenesis including Notch, TGFbeta/BMP, Sonic hedgehog (Shh), FGF, EGF, and Wnt. Despite the widely acknowledged significance of Wnt signalling in embryonic lung development, the role of different Wnt pathways in lung pathologies has been slow to emerge. In this review, we will present a synopsis of current Wnt research with particular attention paid to the role of Wnt signals in lung development and in pulmonary diseases.

Animals↗
PubMed2000

Notch regulates cell fate in the developing pronephros.

The mechanisms that regulate cell fate within the pronephros are poorly understood but are important for the subsequent development of the urogenital system and show many similarities to nephrogenesis in the definitive kidney. Dynamic expression of Notch-1, Serrate-1, and Delta-1 in the developing Xenopus pronephros suggests a role for this pathway in cell fate segregation. Misactivation of Notch signaling using conditionally active forms of either Notch-1 or RBP-J/Su(H) proteins prevented normal duct formation and the proper expression of genetic markers of duct cell differentiation. Inhibition of endogenous Notch signaling elicited the opposite effect. Taken together with the mRNA expression patterns, these data suggest that endogenous Notch signaling functions to inhibit duct differentiation in the dorsoanterior region of the anlage where cells are normally fated to form tubules. In addition, elevated Notch signaling in the pronephric anlage both perturbed the characteristic pattern of the differentiated tubule network and increased the expression of early markers of pronephric precursor cells, Pax-2 and Wilms' tumor suppressor gene (Wt-1). We propose that Notch signaling plays a previously unrecognized role in the early selection of duct and tubule cell fates as well as functioning subsequently to control tubule cell patterning and development.

Animals↗
PubMed2003

Notch signaling augments T cell responsiveness by enhancing CD25 expression.

Notch receptors signal through a highly conserved pathway to influence cell fate decisions. Notch1 is required for T lineage commitment; however, a role for Notch signaling has not been clearly defined for the peripheral T cell response. Notch gene expression is induced, and Notch1 is activated in primary CD4(+) T cells following specific peptide-Ag stimulation. Notch activity contributes to the peripheral T cell response, as inhibition of endogenous Notch activation decreases the proliferation of activated T cells in a manner associated with the diminished production of IL-2 and the expression of the high affinity IL-2R (CD25). Conversely, forced expression of a constitutively active Notch1 in primary T cells results in increased surface expression of CD25, and renders these cells more sensitive to both cognate Ag and IL-2, as measured by cell division. These data suggest an important role for Notch signaling during CD4(+) T cell responses, which operates through augmenting a positive feedback loop involving IL-2 and its high affinity receptor.

Adjuvants, Immunologic↗
PubMed2004

The little R cell that could.

Drosophila eye development provides an excellent model system to study the role of inter-cellular signaling in the specification of unique cell fates. Behavioral screens by Benzer and his colleagues led to the identification of a gene, Sevenless, a receptor tyrosine kinase (RTK) receptor, required for the specification of the UV sensitive R7 cell. Genetic analysis further showed that the Ras/Raf/MAPK pathway function downstream of Sevenless in the specification of R7 fate. Signaling mediated by another RTK, EGFR and Notch have also been shown to function in either an antagonistic or a synergistic manner in the specification of cell fate during eye development. In some instances, these pathways are linked in a sequential manner by the regulation of the expression of Notch ligand, Delta by EGFR, while in others, these pathways function in a combinatorial fashion on enhancer elements to control target gene expression. In this review, we highlight the elegant genetic strategies used by several laboratories in early elucidation of the Sevenless pathway which helped link the RTK receptor to the Ras/Raf/MAPK cascade and discuss how EGFR and Notch signaling pathways are used in a reiterative manner and by combining in different modes, generate sufficient diversity required for the specification of unique cell fates.

Animals↗
PubMed2006

Expression of avian C-terminal binding proteins (Ctbp1 and Ctbp2) during embryonic development.

C-terminal binding proteins (CtBPs) are transcriptional corepressors of mediators of Notch, Wnt, and other signalling pathways. Thus, they are potential players in the control of several developmentally important processes, including segmentation, somitogenesis, and neural tube and limb patterning. We have cloned the avian orthologues of Ctbp1 and Ctbp2 and examined their expression pattern by whole-mount in situ hybridization between Hamburger and Hamilton (HH) stages 3 and 24. Both Ctbp genes show similar expression patterns during embryonic development, and both are detected from HH stage 3 in the developing central nervous system, by HH stage 7 in the paraxial mesoderm and later in the limb bud. In most places, Ctbp1 and Ctbp2 are expressed in overlapping domains. However, there are interesting domains and/or temporal expression patterns that are specific to each Ctbp gene. For instance, Ctbp1 is predominantly expressed in the epiblast, whereas Ctbp2 is in the primitive streak at HH stage 3. However, by HH stage 4, both genes are found in the primitive streak and in the ectoderm. Similarly, although both genes display similar expression patterns in early somitogenesis, in mature somites, Ctbp1 transcripts are located in myotomal cells, whereas Ctbp2 transcripts are observed in dermomyotomal cells. Finally, we found that emigrating neural crest cells express Ctbp2, whereas dorsal root ganglia express Ctbp1. These data suggest that Ctbp1 and Ctbp2 may be functionally redundant in some tissues and have unique functions in other tissues.

Alcohol Oxidoreductases↗
PubMed2002

Mechanisms regulating lineage diversity during mammalian cerebral cortical neurogenesis and gliogenesis.

During mammalian cerebral cortical development, neural stem cells (NSCs) present within periventricular generative zones give rise to successive waves of neurons and radial glia, followed by oligodendrocytes and astrocytes. The molecular and cellular mechanisms that orchestrate these precisely timed and progressive maturational events are still largely undefined. These developmental processes are likely to involve the dynamic interplay of environmental signals, cell-cell interactions and transcriptional regulatory events. The bone morphogenetic proteins (BMPs), an expanding subclass of the transforming growth factor beta cytokine superfamily, may represent an important set of environmental cues for these progressive maturational events because of the broad profiles of developmental expression of the requisite BMP ligands, receptor subunits and intracellular transduction elements, and because of their versatile roles in promoting a spectrum of cellular processes intimately involved in progressive neural fate decisions. The BMPs also interact with complementary regional environmental signals such as the basic fibroblast growth factor (bFGF) and sonic hedgehog (Shh) that promote earlier stages of NSC expansion, self-renewal, lineage restriction and incipient lineage commitment. The ability of these cytokines and trophic signals to act within specific neurodevelopmental contexts may, in turn, depend on the composite actions of cell-cell contact-associated signals, such as Notch-Hes-mediated lateral inhibitory pathways, and additional transcriptional modulatory events, such as those mediated by members of the inhibitor of differentiation (ID) gene family that encode a novel set of negative basic helix-loop-helix (bHLH) transcription factors. In this chapter, we will examine the distinct roles of these different classes of developmental cues in defining the biological properties of an integrated cerebral cortical developmental signaling network. Ongoing studies in this exciting area of mammalian central nervous system (CNS) development will help to identify important molecular and cellular targets for evolving pharmacological, gene and stem cell therapeutic interventions to combat the pathological sequelae of a spectrum of acquired and genetic disorders of the central nervous system.

Animals↗
PubMed2004

The human Ski-interacting protein functionally substitutes for the yeast PRP45 gene.

The PRP45 gene has been identified as encoding a protein involved in mRNA splicing that is essential in Saccharomyces cerevisiae. PRP45's human homolog SKIP has been identified as a mediator of transcriptional programming in a variety of signal transduction pathways including TGFbeta, nuclear hormones, Notch, and retinoblastoma signaling. However, Skip has been also identified in purified spliceosomal complexes but an explicit role in splicing has not been identified in mammalian cells. To determine if the Skip protein could function as a splicing factor we investigated if the SKIP gene could functionally complement the yeast PRP45 gene. We show that SKIP complements the PRP45 deletion and rescues the lethal phenotype. These results show that the human SKIP gene can functionally substitute for the mRNA splicing gene PRP45 of S. cerevisiae.

Amino Acid Sequence↗
PubMed2006

Signature patterns revealed by microarray analyses of mice infected with influenza virus A and Streptococcus pneumoniae.

We used cDNA microarrays to identify differentially expressed genes in mice in response to infections with influenza virus A/PR/8/34 (H1N1) and Streptococcus pneumoniae. Expression microarray analysis showed up-regulation and down-regulation of many genes involved in the defense, inflammatory response and intracellular signaling pathways including chemokine, apoptosis, MAPK, Notch, Jak-STAT, T-cell receptor and complement and coagulation cascades. We have revealed signature patterns of gene expression in mice infected with two different classes of pathogens: influenza virus A and S. pneumoniae. Quantitative real-time RT-PCR results confirmed microarray results for most of the genes tested. These studies document clear differences in gene expression profiles between mice infected with influenza virus A and S. pneumoniae. Identification of genes that are differentially expressed after respiratory infections can provide insights into the mechanisms by which the host interacts with different pathogens, useful information about stage of diseases and selection of suitable targets for early diagnosis and treatments. The advantage of this novel approach is that the detection of pathogens is based on the differences in host gene expression profiles in response to different pathogens instead of detecting pathogens directly.

Animals↗