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.

SourceResearch connectionFrom yearThrough year

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

At least 1,153 records · Page 64Linked to original sources

PubMed2005

Off limits--integrins holding boundaries in somitogenesis.

Borders are essential for demarcating repeated structures such as somites during vertebrate development. Two recent articles describe roles for Integrinalpha5 and its ligand Fibronectin1 in zebrafish anterior intersomitic boundary formation and link them to Notch and Eph-Ephrin pathways in epithelialization of somite boundary cells. Together with these pathways, Integrinalpha5 and Fibronectin1 orchestrate the orderly formation of somite and later myotome borders. These studies shed light on components downstream of the periodic segmentation mechanism - the 'segmentation clock' - in somitogenesis.

Animals↗

PubMed2000

The midline glia of Drosophila: a molecular genetic model for the developmental functions of glia.

The Midline Glia of Drosophila are required for nervous system morphogenesis and midline axon guidance during embryogenesis. In origin, gene expression and function, this lineage is analogous to the floorplate of the vertebrate neural tube. The expression or function of over 50 genes, summarised here, has been linked to the Midline Glia. Like the floorplate, the cells which generate the Midline Glia lineage, the mesectoderm, are determined by the interaction of ectoderm and mesoderm during gastrulation. Determination and differentiation of the Midline Glia involves the Drosophila EGF, Notch and segment polarity signaling pathways, as well as twelve identified transcription factors. The Midline Glia lineage has two phases of cell proliferation and of programmed cell death. During embryogenesis, the EGF receptor pathway signaling and Wrapper protein both function to suppress apoptosis only in those MG which are appropriately positioned to separate and ensheath midline axonal commissures. Apoptosis during metamorphosis is regulated by the insect steroid, Ecdysone. The Midline Glia participate in both the attraction of axonal growth cones towards the midline, as well as repulsion of growth cones from the midline. Midline axon guidance requires the Drosophila orthologs of vertebrate genes expressed in the floorplate, which perform the same function. Genetic and molecular evidence of the interaction of attractive (Netrin) and repellent (Slit) signaling is reviewed and summarised in a model. The Midline Glia participate also in the generation of extracellular matrix and in trophic interactions with axons. Genetic evidence for these functions is reviewed.

Animals↗

PubMed1997

Graded amounts of Xenopus dishevelled specify discrete anteroposterior cell fates in prospective ectoderm.

Signals emitted from the prospective dorsal marginal zone (the organizer) are thought to specify neuroectodermal cell fates along the anteroposterior (AP) axis, but the mechanisms underlying this signaling event remain to be elucidated. To assess the effect of Xenopus Dishevelled (Xdsh), a proposed component of the Wnt, Notch and Frizzled signal transduction pathways, on AP axis determination, it was supplied in varying doses to presumptive ectodermal cells. Two-fold increments in levels of microinjected Xdsh mRNA revealed a gradual shift in cell fates along the AP axis. Lower doses of Xdsh mRNA activated anterior neuroectodermal markers, XAG1 and Xotx2, whereas the higher doses induced more posterior neural tissue markers such as En2, Krox20 and HoxB9. At the highest dose of Xdsh mRNA, explants contained maximal amount of HoxB9 transcripts and developed notochord and somites. When compared with Xdsh, Xwnt8 mRNA also activated anterior neuroectodermal markers, but failed to elicit mesoderm formation. Analysis of explants overexpressing Xdsh at the gastrula stage revealed activation of several organizer-specific genes which have been implicated in determination of neural tissue (Xotx2, noggin, chordin and follistatin). Whereas Goosecoid, Xlim1 and Xwnt8 were not induced in these explants, another early marginal zone marker, Xbra, was activated at the highest level of Xdsh mRNA. These observations suggest that the effects of Xdsh on AP axis specification may be mediated by combinatorial action of several early patterning genes. Increasing levels of Xdsh mRNA activate posterior markers, whereas increasing amounts of the organizer stimulate the extent of anterior development (Stewart, R.M. and Gerhart, J.C. (1990) Development 109, 363-372). These findings argue against induction of the entire organizer by Xdsh in ectodermal cells and implicate signal transduction pathways involving Xdsh in AP axis determination. Thus, different levels of a single molecule, Xdsh, can specify distinct cell states along the AP axis.

Actins↗

PubMed2003

Regulatory coding of lymphoid lineage choice by hematopoietic transcription factors.

During lymphopoiesis, precursor cells negotiate a complex regulatory space, defined by the levels of several competing and cross-regulating transcription factors, before arriving at stable states of commitment to the B-, T- and NK-specific developmental programs. Recent perturbation experiments provide evidence that this space has three major axes, corresponding to the PU.1 versus GATA-1 balance, the intensity of Notch signaling through the CSL pathway, and the ratio of E-box transcription factors to their Id protein antagonists.

Animals↗

PubMed2003

Tissue-specific gene expression and ecdysone-regulated genomic networks in Drosophila.

During insect metamorphosis, each tissue displays a unique physiological and morphological response to the steroid hormone 20-hydroxyecdysone (ecdysone). We assayed gene expression in five tissues during metamorphosis onset. Larval-specific tissues display major changes in genome-wide expression profiles, whereas tissues that survive into adulthood display few changes. In one larval tissue, the salivary gland, we used a computational approach to identify a regulatory motif and a cognate transcription factor involved in regulating a set of coexpressed genes. During the metamorphosis of another tissue, the midgut, genes encoding factors from the hedgehog, Notch, EGF, dpp, and wingless pathways are activated by the ecdysone regulatory network. Mutation of the ecdysone receptor abolishes their induction. Cell cycle genes are also activated during the initiation of midgut metamorphosis, and they are also dependent on ecdysone signaling. These results establish multiple new connections between the ecdysone regulatory network and other well-studied regulatory networks.

Amino Acid Sequence↗

PubMed2004

Cornelia de Lange syndrome is caused by mutations in NIPBL, the human homolog of Drosophila melanogaster Nipped-B.

Cornelia de Lange syndrome (CdLS; OMIM 122470) is a dominantly inherited multisystem developmental disorder characterized by growth and cognitive retardation; abnormalities of the upper limbs; gastroesophageal dysfunction; cardiac, ophthalmologic and genitourinary anomalies; hirsutism; and characteristic facial features. Genital anomalies, pyloric stenosis, congenital diaphragmatic hernias, cardiac septal defects, hearing loss and autistic and self-injurious tendencies also frequently occur. Prevalence is estimated to be as high as 1 in 10,000 (ref. 4). We carried out genome-wide linkage exclusion analysis in 12 families with CdLS and identified four candidate regions, of which chromosome 5p13.1 gave the highest multipoint lod score of 2.7. This information, together with the previous identification of a child with CdLS with a de novo t(5;13)(p13.1;q12.1) translocation, allowed delineation of a 1.1-Mb critical region on chromosome 5 for the gene mutated in CdLS. We identified mutations in one gene in this region, which we named NIPBL, in four sporadic and two familial cases of CdLS. We characterized the genomic structure of NIPBL and found that it is widely expressed in fetal and adult tissues. The fly homolog of NIPBL, Nipped-B, facilitates enhancer-promoter communication and regulates Notch signaling and other developmental pathways in Drosophila melanogaster.

Animals↗

PubMed2006

Early evolution of animal cell signaling and adhesion genes.

In stark contrast to the rapid morphological radiation of eumetazoans during the Cambrian explosion, the simple body plan of sponges (Phylum Porifera) emerged from the Cambrian relatively unchanged. Although the genetic and developmental underpinnings of these disparate evolutionary outcomes are unknown, comparisons between modern sponges and eumetazoans promise to reveal the extent to which critical genetic factors were present in their common ancestors. Two particularly interesting classes of genes in this respect are those involved in cell signaling and adhesion. These genes help guide development and morphogenesis in modern eumetazoans, but the timing and sequence of their origins is unknown. Here, we demonstrate that the sponge Oscarella carmela, one of the earliest branching animals, expresses core components of the Wnt, transforming growth factor beta, receptor tyrosine kinase, Notch, Hedgehog, and Jak/Stat signaling pathways. Furthermore, we identify sponge homologs of nearly every major eumetazoan cell-adhesion gene family, including those that encode cell-surface receptors, cytoplasmic linkers, and extracellular-matrix proteins. From these data, we infer that key signaling and adhesion genes were in place early in animal evolution, before the divergence of sponge and eumetazoan lineages.

Animals↗

PubMed2001

Ethanol hypersensitivity and olfactory discrimination defect in mice lacking a homolog of Drosophila neuralized.

Neurogenic genes in the Notch receptor-mediated signaling pathway play important roles in neuronal cell fate specification as well as neuronal differentiation. The Drosophila neuralized gene is one of the neurogenic genes. We have cloned a mouse homolog of Drosophila neuralized, m-neu1, and found that the m-neu1 transcript is expressed in differentiated neurons. Mice deficient for m-neu1 are viable and morphologically normal, but exhibit specific defects in olfactory discrimination and hypersensitivity to ethanol. These findings reveal an essential role of m-neu1 in ensuring proper processing of certain information in the adult brain.

Amino Acid Sequence↗

PubMed1996

Identification of AF-6 and canoe as putative targets for Ras.

Ras (Ha-Ras, Ki-Ras, N-Ras) is implicated in the regulation of various cell functions such as gene expression and cell proliferation downstream from specific extracellular signals. Here, we partially purified a Ras-interacting protein with molecular mass of about 180 kDa (p180) from bovine brain membrane extract by glutathione S-transferase (GST)-Ha-Ras affinity column chromatography. This protein bound to the GTP gamma S (guanosine 5'-(3-O-thio)triphosphate, a nonhydrolyzable GTP analog).GST-Ha-Ras affinity column but not to those containing GDP.GST-Ha-Ras or GTP gamma S.GST-Ha-Ras with a mutation in the effector domain (Ha-RasA38). The amino acid sequences of the peptides derived from p180 were almost identical to those of human AF-6 that is identified as the fusion partner of the ALL-1 protein. The ALL-1/AF-6 chimeric protein is the critical product of the t (6:11) abnormality associated with some human leukemia. AF-6 has a GLGF/Dlg homology repeat (DHR) motif and shows a high degree of sequence similarity with Drosophila Canoe, which is assumed to function downstream from Notch in a common developmental pathway. The recombinant N-terminal domain of AF-6 and Canoe specifically interacted with GTP gamma S.GST-Ha-Ras. The known Ras target c-Raf-1 inhibited the interaction of AF-6 with GTP gamma S.GST-Ha-Ras. These results indicate that AF-6 and Canoe are putative targets for Ras.

Amino Acid Sequence↗

PubMed2004

NIPBL mutational analysis in 120 individuals with Cornelia de Lange syndrome and evaluation of genotype-phenotype correlations.

The Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphia, upper-extremity malformations, hirsutism, cardiac defects, growth and cognitive retardation, and gastrointestinal abnormalities. Both missense and protein-truncating mutations in NIPBL, the human homolog of the Drosophila melanogaster Nipped-B gene, have recently been reported to cause CdLS. The function of NIPBL in mammals is unknown. The Drosophila Nipped-B protein facilitates long-range enhancer-promoter interactions and plays a role in Notch signaling and other developmental pathways, as well as being involved in mitotic sister-chromatid cohesion. We report the spectrum and distribution of NIPBL mutations in a large well-characterized cohort of individuals with CdLS. Mutations were found in 56 (47%) of 120 unrelated individuals with sporadic or familial CdLS. Statistically significant phenotypic differences between mutation-positive and mutation-negative individuals were identified. Analysis also suggested a trend toward a milder phenotype in individuals with missense mutations than in those with other types of mutations.

Amino Acid Sequence↗

PubMed2001

Notch signaling is a direct determinant of keratinocyte growth arrest and entry into differentiation.

The role of Notch signaling in growth/differentiation control of mammalian epithelial cells is still poorly defined. We show that keratinocyte-specific deletion of the Notch1 gene results in marked epidermal hyperplasia and deregulated expression of multiple differentiation markers. In differentiating primary keratinocytes in vitro endogenous Notch1 is required for induction of p21WAF1/Cip1 expression, and activated Notch1 causes growth suppression by inducing p21WAF1/Cip1 expression. Activated Notch1 also induces expression of 'early' differentiation markers, while suppressing the late markers. Induction of p21WAF1/Cip1 expression and early differentiation markers occur through two different mechanisms. The RBP-Jkappa protein binds directly to the endogenous p21 promoter and p21 expression is induced specifically by activated Notch1 through RBP-Jkappa-dependent transcription. Expression of early differentiation markers is RBP-Jkappa-independent and can be induced by both activated Notch1 and Notch2, as well as the highly conserved ankyrin repeat domain of the Notch1 cytoplasmic region. Thus, Notch signaling triggers two distinct pathways leading to keratinocyte growth arrest and differentiation.

Animals↗

PubMed2004

Recent advances in defining the hematopoietic stem cell niche.

PURPOSE OF REVIEW: Hematopoietic stem cells are thought to reside in discrete cellular spaces termed "niches." The cellular elements and matrix surrounding the stem cell within the niche constitute the microenvironment. The purpose of this review is to discuss recent reports that have begun to elucidate the geographic location, key cellular type, and molecular mechanisms operating in stem cell niches. RECENT FINDINGS: Studies that have revealed the osteoblast as the key in vivo cellular element of the adult stem cell niche are the most significant recent findings. Additional studies have highlighted the importance of the Notch and Wingless (Wnt) signaling pathways in the hematopoietic microenvironment. Genomewide expression screens have been used to perform molecular profiling of stromal cell lines that serve as surrogate stem cell niches. These profiles have revealed novel regulatory molecules and have reinforced the roles of classic developmental morphogens in the niche space. The transcriptional profiling from these screens suggests that it is highly unlikely that a single factor or signal transduction pathway will control stem cell properties. SUMMARY: This review highlights the recent advances made toward elucidating the cellular and molecular attributes of the hematopoietic stem cell niche. Complete knowledge of the cellular architecture and molecular mechanisms in stem cell niches is essential to understanding the basic stem cell behaviors of self-renewal and differentiation.

Animals↗

PubMed1999

EST analysis of gene expression in early cleavage-stage sea urchin embryos.

A set of 956 expressed sequence tags derived from 7-hour (mid-cleavage) sea urchin embryos was analyzed to assess biosynthetic functions and to illuminate the structure of the message population at this stage. About a quarter of the expressed sequence tags represented repetitive sequence transcripts typical of early embryos, or ribosomal and mitochondrial RNAs, while a majority of the remainder contained significant open reading frames. A total of 232 sequences, including 153 different proteins, produced significant matches when compared against GenBank. The majority of these identified sequences represented 'housekeeping' proteins, i.e., cytoskeletal proteins, metabolic enzymes, transporters and proteins involved in cell division. The most interesting finds were components of signaling systems and transcription factors not previously reported in early sea urchin embryos, including components of Notch and TGF signal transduction pathways. As expected from earlier kinetic analyses of the embryo mRNA populations, no very prevalent protein-coding species were encountered; the most highly represented such sequences were cDNAs encoding cyclins A and B. The frequency of occurrence of all sequences within the database was used to construct a sequence prevalence distribution. The result, confirming earlier mRNA population analyses, indicated that the poly(A) RNA of the early embryo consists mainly of a very complex set of low-copy-number transcripts.

Animals↗

PubMed2006

Concise review: recent advances on the significance of stem cells in tissue regeneration and cancer therapies.

In this study, we report on recent advances on the functions of embryonic, fetal, and adult stem cell progenitors for tissue regeneration and cancer therapies. We describe new procedures for derivation and maturation of these stem cells into the tissue-specific cell progenitors. The localization of the adult stem cells and their niches, as well as their implication in the tissue repair after injuries and during cancer progression, are also described. The emphasis is on the interactions among certain developmental signaling factors, such as hormones, epidermal growth factor, hedgehog, Wnt/beta-catenin, and Notch. These factors and their pathways are involved in the stringent regulation of the self-renewal and/or differentiation of adult stem cells. Novel strategies for the treatment of both diverse degenerating disorders, by cell replacement, and some metastatic cancer types, by molecular targeting multiple tumorigenic signaling elements in cancer progenitor cells, are also illustrated.

Animals↗

PubMed2026

Genome-wide cis-expression Quantitative Trait Loci (eQTL) and transcriptomic signals reveal distinct molecular regulation across correlated feed efficiency traits.

INTRODUCTION: Feed efficiency (FE) is a complex trait which determines livestock production profitability, yet the molecular mechanisms behind it remain unclear. This study investigated the blood transcriptomic profile of lambs, alongside genotype data with the aim to uncover the genetic basis of FE traits such as absolute dry matter intake (DMIabsolute), DMI adjusted for body size (DMIadjusted), average daily live weight gain (ADG), and residual feed intake (RFI). MATERIALS AND METHODS: Bulk RNA-Seq and genotype data were analysed using three complementary approaches: differential gene expression (DGE) analysis, weighted gene co-expression network analysis (WGCNA), and cis-expression Quantitative Trait Loci (cis-eQTL) mapping. These methods were used independently to identify genes and regulatory networks associated with FE traits and to investigate evidence supporting multi-trait candidate gene selection. RESULTS: DGE analysis revealed 2, 24, 85 and 4 differentially expressed genes for DMIabsolute, DMIadjusted, ADG, and RFI (Padjusted < 0.05), functionally enriched in sensory perception, ATP-dependent chromatin remodeling, Notch signaling and immune response pathways. 9 gene modules significantly associated with the FE traits (P ≤ 0.05) with correlations ranging from r = -0.56 to 0.49, were identified using WGCNA. Single nucleotide polymorphism (SNP)-level cis-eQTL analysis identified 93 eSNPs associated with 74 genes (false discovery rate (FDR) < 0.05), while permutation-derived gene level analysis identified 280 eGenes (FDR < 0.2, empirical P < 0.03). Across the three analyses, applying thresholds of DGE (Padjusted < 0.05), WGCNA (correlation, P ≤ 0.05), and cis-eQTL gene-level significance (empirical P < 0.05), multiple overlapping genes were identified including DNMT3A, KANSL1, NCOR1 for DMIadjusted, ACOX2, FANCF, CIMIP2B, LOC101115106, ARMH2, LOC132657496 for ADG, and LOC114114576 for RFI representing regulators of variations in FE. DISCUSSION: The integration of DGE, WGCNA, and cis-eQTL analyses identified key genes and regulatory mechanisms associated with variation in FE traits. These results highlight that integrated multi-trait candidate gene identification approaches can reveal key genes that lower feed intake while maintaining animal growth, supporting breeding strategies aimed at improving efficiency and long-term economic sustainability in sheep.

average daily gain (ADG)↗

PubMed1998

Homeotic proboscipedia cell identity functions respond to cell signaling pathways along the proximo-distal axis.

To better understand how the different cell identities composing a segment are attributed and coordinated under the control of a single homeotic selector gene, we examined dose-sensitive homeotic phenotypes associated with gain-of-function and loss-of-function mutations of the homeotic gene proboscipedia (pb; Hox-A2/-B2). We then employed dose-sensitive segment and cell identity phenotypes resulting from ectopic proboscipedia expression to screen for other interacting loci. We find that pb, as well as the homeotic loci Ultrabithorax, Sex combs reduced and Antennapedia, respond to positional information along the proximo-distal axis. This response for pb implicates at least two signal transduction pathways, those involving Ras1 and Notch.

Animals↗

PubMed2003

Notch and Presenilin: regulated intramembrane proteolysis links development and degeneration.

Intensive studies of three proteins--Presenilin, Notch, and the amyloid precursor protein (APP)--have led to the recognition of a direct intersection between early development and late-life neurodegeneration. Notch signaling mediates many different intercellular communication events that are essential for determining the fates of neural and nonneural cells during development and in the adult. The Notch receptor acts in a core pathway as a membrane-bound transcription factor that is released to the nucleus by a two-step cleavage mechanism called regulated intramembrane proteolysis (RIP). The second cleavage is effected by Presenilin, an unusual polytopic aspartyl protease that apparently cleaves Notch and numerous other single-transmembrane substrates within the lipid bilayer. Another Presenilin substrate, APP, releases the amyloid ss-protein that can accumulate over time in limbic and association cortices and help initiate Alzheimer's disease. Elucidating the detailed mechanism of Presenilin processing of membrane proteins is important for understanding diverse signal transduction pathways and potentially for treating and preventing Alzheimer's disease.

Alzheimer Disease↗

PubMed2005

Expression of a novel zebrafish zinc finger gene, gli2b, is affected in Hedgehog and Notch signaling related mutants during embryonic development.

Gli zinc-finger proteins are known as downstream mediators of the evolutionary conserved Hedgehog pathway. In zebrafish, gli2 functions differently from Gli2 in mammals. This difference could be due to the gli2 duplication in teleosts evolution and partial redundancy between two duplicated genes. Here, we report a novel zebrafish gli2-like cDNA. Its structure, genetic location, and distinct expression pattern in the central nervous system suggested that this gene might represent a second gli2 of teleosts, and we named it gli2b. gli2b was expressed in the neural keel, excluding the forebrain-midbrain boundary, while gli2 expression complemented this pattern. After 24 hours postfertilization, several specific domains of gli2b expression were observed in the lateral and medial hindbrain and hypothalamus. In mutants affecting the Hedgehog and Notch signaling pathways, gli2b expression was either disrupted or extended in different regions.

Amino Acid Sequence↗