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Results for “Notch pathway”

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At least 865 records · Page 48Linked to original sources
PubMed2006

Polypyrimidine tract binding protein regulates IRES-mediated gene expression during apoptosis.

During apoptosis there is a substantial reduction in the rate of protein synthesis, and yet some mRNAs avoid this translational inhibition. To determine the impact that receptor-mediated cell death has on the translational efficiency of a large number of mRNAs, translational profiling was performed on MCF7 cells treated with the apoptosis-inducing ligand TRAIL. Our data indicate that approximately 3% of mRNAs remain associated with the polysomes in apoptotic cells, and genes that are involved in transcription, chromatin modification/remodeling, and the Notch signaling pathway are particularly prevalent among the mRNAs that evade translational inhibition. Internal ribosome entry segments (IRESs) were identified in several of the mRNAs that remained associated with the polysomes during apoptosis, and, importantly, these IRESs functioned efficiently in apoptotic cells. Finally, the data showed that polypyrimidine tract binding protein (PTB, a known IRES trans-acting factor or ITAF) is pivotal in regulating the apoptotic process by controlling IRES function.

5' Untranslated Regions↗
PubMed2006

Essential role of RBP-Jkappa in activation of the K8 delayed-early promoter of Kaposi's sarcoma-associated herpesvirus by ORF50/RTA.

KSHV K8 gene is activated by virally encoded transactivator RTA in delayed-early stage of viral reactivation. Three RTA-responsive elements (RREs) were identified in the promoter. Among them, RRE-II was found to be the most critical cis-acting element for RTA transactivation. In this report, the mechanism underlying RTA-mediated activation of the K8 delayed-early promoter was investigated. A DNA affinity purification study demonstrated that RRE-II was bound by cellular protein RBP-Jkappa, a sequence-specific DNA binding protein and a primary target of the Notch signaling pathway. Inspection of the RRE-II sequence revealed a potential recognition sequence for RBP-Jkappa (GTGAGAA) between the nucleotides -102 and -108 relative to the transcription initial site. Removal or mutation of the motif abolished RBP-Jkappa binding to the K8 promoter and as a consequence, RTA failed to bind to and activate the promoter. An essential role of RBP-Jkappa in the transcription of the K8 promoter was demonstrated by diminishment of the promoter activity in RBP-Jkappa-null murine embryonic fibroblasts. Taken together, RTA activates the K8 promoter through an indirect binding mechanism, i.e. being recruited to the K8 promoter through interaction with RBP-Jkappa bound to an RBP-Jkappa motif in the promoter.

Animals↗
PubMed2004

Murine numb regulates granule cell maturation in the cerebellum.

Notch is a key regulator of vertebrate neurogenesis and the cytoplasmic adaptor protein Numb is a modulator of the Notch signaling pathway. To address the role of murine Numb in development of the central nervous system, we used a conditional gene ablation approach. We show that Numb is involved in the maturation of cerebellar granule cells. Although the specification of neural cell fates in the cerebellum is not affected in the absence of Numb, the transition from a mitotic progenitor to a mature granule cell is aberrant and migration of postmitotic granule cells to the internal granule cell layer is delayed. In some animals, this results in a complete agenesis of granule cells and a strong ataxia. We confirmed these findings in vitro and found that Numb-deficient cerebellar progenitor cells show a marked delay in granule cell maturation. Our results suggest that Numb plays a role in the transition of a mitotic progenitor to a fully differentiated granule cell in the cerebellum. In addition, the maturation of Purkinje cells is also delayed in Numb-deficient mice.

Animals↗
PubMed2004

Mother-daughter precursor cell fate transformation after Cdc2 down-regulation in the Drosophila bristle lineage.

The Drosophila bristle lineage is an excellent system in which to study how cell cycle and fate determination are synchronized in invariant cell lineages. In this model, five different cells arise from a single precursor cell, pI, after four asymmetric cell divisions. Cell diversity is achieved by the asymmetric segregation of cell determinants, such as Numb and Neuralized (Neur), resulting in differential activation of the Notch (N) pathway. We show that down-regulation of Cdc2, by over-expressing Tribbles, Dwee1, and Dmyt1 (three negative regulators of Cdc2) or by using thermo-sensitive Cdc2 mutant flies, delayed pI mitosis, and altered the polarity and the number of subsequent cell divisions. These modifications were associated with a mother-daughter cell fate transformation as the pI cell acquired the identity of the secondary precursor cell, pIIb. This type of change in cell identity only occurred when the N signaling pathway was inactive since ectopic N signaling transformed pI to pIIa-progeny fate. These transformations in cell identity suggest that, although synchronized, cell cycle and fate determination are independent phenomena in the bristle lineage.

Animals↗
PubMed2006

Expression of constitutively active Notch1 in male genital tracts results in ectopic growth and blockage of efferent ducts, epididymal hyperplasia and sterility.

The Notch signaling pathway is involved in a variety of developmental processes. Here, we characterize the phenotypes developing in the reproductive organs of male transgenic (Tg) mice constitutively expressing the activated mouse Notch1 intracellular domain (Notch1(intra)) under the regulatory control of the mouse mammary tumor virus (MMTV) long terminal repeat (LTR). Tg expression was detected in testis, vas deferens and epididymis by Northern blot analysis. In situ hybridization with a Notch1-specific probe lacked sensitivity to detect expression in normal-appearing cells, but demonstrated expression in hyperplastic epithelial cells of the vas deferens, epididymis and efferent ducts. Tg males from three independent founder lines were sterile. Histological analysis of reproductive organs of young Tg males (postnatal ages 8 and 21) showed no difference compared to those of non-Tg males. In contrast, in adult Tg mice from day 38 onwards, the efferent ducts, the vas deferens and most epididymal segments revealed bilateral epithelial cell hyperplasia with absence of fully differentiated epithelial cells. Electron microscopy confirmed the uniformly undifferentiated state of these cells. Immunohistochemistry with anti-PCNA antibody also revealed enhanced proliferation of Tg epididymis. In adult Tg testis, the different generations of germ cells of seminiferous tubules appeared normal, although some tubules were highly dilated and revealed an absence of early and/or late spermatids. The epithelial cells of the Tg tubuli recti and rete testis were not abnormal, but the rete testis was highly dilated and contained numerous spermatozoa, suggesting a downstream blockage. Consistent with a blockage of efferent ducts often seen at the rete testis/efferent duct interface, spermatozoa were absent in epididymis of all adult Tg mice and in all highly hyperplastic efferent duct tubules of these Tg mice. Such a blockage was visualized by injection of Evans blue dye into the rete testis lumen. Finally, the presence of ectopic hyperplastic efferent duct tubules was observed within the testicular parenchyma itself, outside their normal territory, suggesting that Notch1 signaling is involved in the establishment of these borders. This phenotype seems to represent a novel developmental defect in mammals. Together, these results show that constitutive Notch1 signaling significantly affects the development of male reproductive organs.

Animals↗
PubMed2003

Differentiation of bone marrow cells into cells that express liver-specific genes in vitro: implication of the Notch signals in differentiation.

Bone marrow (BM) stem cells have been shown to differentiate into liver cells. It remains difficult to sort and culture BM stem cells, and the gene expression of liver-specific proteins in these cells has not been fully investigated. We used a negative selective magnetic cell separation system to obtain stem cell-enriched BM cells. The cells obtained were cultured with hepatocytes or with hepatocyte growth factor (HGF), and the differentiation of BM cells into cells expressing liver-specific genes, hepatocyte nuclear factor (HNF) 1alpha, cytokeratin (CK) 8, alpha-fetoprotein (AFP), and albumin was investigated by the reverse transcription-polymerase chain reaction. We also investigated the gene expressions of Notch receptor-1 (Notch-1) and its ligand Jagged-1 in BM cell differentiation. Sorted BM cells showed positive for Sca-1 (Ataxin-1) by immunofluorescence staining. Fluorescence activated cell sorter analysis showed that 32.6% of sorted BM cells had a high level of expression of the hematopoietic stem cell marker CD90 (Thy-1). When cultured with hepatocytes, these cells expressed the liver-specific genes HNF1alpha and CK8 on culture day 3, AFP and albumin on culture day 7. When cultured with HGF (20ng/ml), the cells expressed HNF1alpha on day 3 and CK8 on day 7. Gene expressions of Notch-1 and Jagged-1 were detected in cultured BM cells on day 3. These results suggest that the negative selective magnetic cell separation system is useful for the rapid preparation of stem cell-enriched BM cells, and that the Notch signaling pathway plays a role in BM cell differentiation into a hepatocyte lineage in vitro.

Animals↗
PubMed2003

Isolation and expression of Napor/CUG-BP2 in embryo development.

The human neuroblastoma apoptosis-related RNA-binding protein NAPOR is an ELAV-like RNA-binding protein with three characteristic RNA recognition motifs (RRMs). We report here the cloning and characterization of a zebrafish Napor that has a high sequence homology to human NAPOR protein. Whole-mount in situ hybridization analysis revealed that zebrafish napor is dynamically expressed in early development. In addition to its maternal expression, napor transcripts were detected in adaxial mesoderm cells and lateral neural plate cells at early somite stages. By 10-somite stage, napor expression was restricted to the central nervous system, having a specific expression domain of rhombomere 5 in the hindbrain. In 24 hpf embryo, napor was expressed in subsets of differentiating neural cells in the forebrain and hindbrain as well as somitic muscle cells. The number of napor-expressing neural cells was greatly increased in the mind bomb mutant that has neurogenic phenotype resulting from deficits in the Notch signaling pathway. Furthermore, overexpression of napor by RNA microinjection resulted in severe defects in nervous system and gastrulation, suggesting the need for tight control of napor gene regulation during embryo development.

Amino Acid Sequence↗
PubMed2000

Segmentation of the paraxial mesoderm and vertebrate somitogenesis.

Somites are the most obviously segmented features of the vertebrate embryo. Although the way segmentation is achieved in the fly is now well described, little was known about the molecular mechanisms underlying vertebrate somitogenesis. Through the recent identification of genes important for vertebrate somitogenesis and the analysis of their function, several theoretical models accounting for somitogenesis such as the clock and wavefront model, which have been proposed over the past 20 years, are now starting to receive experimental support. A molecular clock linked to somitogenesis has been identified which might act as a periodicity generator in the presomitic cells. This temporal periodicity is then translated into a tightly controlled spatial periodicity which is revealed by the expression of several genes. Analysis of mouse mutants in the Notch-Delta pathway suggest that this signaling mechanism might play an important role at this level. The final step of the cascade is to translate these genetically specified segments into morphological units: the somites. Importantly, these studies have helped in dissociating the segmentation and the somitogenesis processes in vertebrates. In addition, although segmentation was classically thought to have arisen independently in protostomes and deuterostomes, recent evidence suggests that part of the segmentation machinery might actually have been conserved. The conservation of segmentation mechanisms reported in the fly such as the pair-rule pattern, however, remain a subject of controversy.

Animals↗
PubMed2000

Demarcation of early mammalian cortical development by differential expression of fringe genes.

Fringe has originally been found in Drosophila as a gene encoding a putative secreted protein which regulates the sensitivity of Notch signaling pathway to different ligands. We show that three members of murine fringe gene family, Lunatic fringe (L-fng), Manic fringe (M-fng) and Radical fringe (R-fng), show related patterns of expression in the developing cerebral wall. L-fng is expressed in immature cells in the ventricular zone. M-fng is upregulated transiently in maturing neurons when they leave the ventricular zone (VZ). R-fng is upregulated in more mature neurons when they enter the preplate and cortical plate. These patterns suggest that the transition from immature to mature neurons involves sequential changes in the member of fringe family genes expressed. More detailed expression analyses of fringe genes and immunohistochemistry for neuron-specific class III beta-tubulin suggest a mode of neurogenesis which might underlie the histogenesis of the cerebral cortex. A proliferative population situated outside of the VZ is defined as M-fng-positive/BrdU-positive cells, which constitutes about 10-20% of the total S-phase cells in the cerebral wall of embryonic day 10.5-12.5. We found that M-fng is expressed in mitotic figures outside the VZ and some of them react with the antibody against class III beta-tubulin. These observations suggest that a significant number of proliferative cells exist outside the VZ, which supply neurons during early cortical development.

Animals↗
PubMed2001

Role of the multifunctional CDP/Cut/Cux homeodomain transcription factor in regulating differentiation, cell growth and development.

CDP/Cux/Cut proteins are an evolutionarily conserved family of proteins containing several DNA binding domains: one Cut homeodomain and one, two or three Cut repeats. In Drosophila melanogaster, genetic studies indicated that Cut functions as a determinant of cell-type specification in several tissues, notably in the peripheral nervous system, the wing margin and the Malpighian tubule. Moreover, Cut was found to be a target and an effector of the Notch signaling pathway. In vertebrates, the same functions appear to be fulfilled by two cut-related genes with distinct patterns of expression. Cloning of the cDNA for the CCAAT-displacement protein (CDP) revealed that it was the human homologue of Drosophila Cut. CDP was later found be the DNA binding protein of the previously characterized histone nuclear factor D (HiNF-D). CDP and its mouse counterpart, Cux, were also reported to interact with regulatory elements from a large number of genes, including matrix attachment regions (MARs). CDP/Cut proteins were found generally to function as transcriptional repressors, although a participation in transcriptional activation is suggested by some data. Repression by CDP/Cut involves competition for binding site occupancy and active repression via the recruitment of a histone deacetylase activity. Various combinations of Cut repeats and the Cut homeodomains can generate distinct DNA binding activities. These activities are elevated in proliferating cells and decrease during terminal differentiation. One activity, involving the Cut homeodomain, is upregulated in S phase. CDP/Cut function is regulated by several post-translational modification events including phosphorylation, dephosphorylation, and acetylation. The CUTL1 gene in human was mapped to 7q22, a chromosomal region that is frequently rearranged in various cancers.

Animals↗
PubMed2003

Dynamic gene expression during the onset of myoblast differentiation in vitro.

Skeletal myogenesis is a well-studied differentiation process. However, despite the identification and functional characterization of the myogenic basic HLH transcription factors, molecular details are still lacking. With the advent of microarray technology, it has become possible to look at changes in gene expression profiles in a biological process on an unprecedented scale. In this study, we applied this technology to profile gene expression during the in vitro differentiation of an established myoblast cell line, C2C12. We report over 1500 genes whose expression is altered when these cells differentiate, including 624, or about 40% of the total number of genes, with unknown functions. This analysis reveals the existence of 12 groups of coordinately regulated genes that are expressed in temporal waves of gene expression prior to the transcriptional induction of myogenin. Among these are multiple families of transcription factors that are important for the process of myogenesis. In addition, the induction of the Notch signaling pathway suggests that previously unappreciated intercellular signaling occurs during myogenic differentiation. These results provide a molecular description of the skeletal myogenesis up to the activation of myogenin.

Animals↗
PubMed2001

The COE--Collier/Olf1/EBF--transcription factors: structural conservation and diversity of developmental functions.

One major conclusion of studies in Developmental Biology during the last two decades is that, despite profound anatomical differences, the building of vertebrate and arthropod bodies relies on the same fundamental molecular networks, including conserved cell signalling and transcription-regulatory cascades. Rodent Early B-Cell Factor/Olfactory-1 and Drosophila Collier belong to a recently defined, novel family of transcription factors, the Collier/Olf1/EBF (COE) proteins which have a unique DNA-binding domain. Early investigations revealed that, despite their high degree of sequence identity, the different vertebrate and invertebrate COE proteins play a variety of developmental roles. We review here the current evidence for this diversity of COE functions, including in the specification and differentiation of various neuronal populations. We also discuss the existence of an evolutionarily conserved pathway linking Notch signalling and COE regulatory functions in various developmental decisions.

Amino Acid Sequence↗
PubMed2002

Embryonic expression of mSharp-1/mDEC2, which encodes a basic helix-loop-helix transcription factor.

We describe the expression pattern of mouse Sharp-1 (mSharp-1), a member of the basic helix-loop-helix (bHLH) family of transcription factors. mSharp-1 belongs to the Hairy/Enhancer of Split (E(Spl)) subfamily of bHLH factors that are key targets of the Notch signaling pathway and exhibits the highest sequence identity with Stra13. RNA in situ hybridization analysis from embryonic day 7.5 (E7.5) to E16.5 revealed specific expression of mSharp-1 in several developing organs during mouse embryogenesis. In early stage embryos (E8.5-E12.5), mSharp-1 is expressed in specific dorsal regions of the developing brain, the heart, the developing eye and olfactory system, as well as in the limb buds. At later stages (E12.5-E16.5), mSharp-1 is also expressed in the liver, prevertebrae, and the developing adrenal and thyroid glands. The diversity of its expression pattern suggests that mSharp-1 may regulate the differentiation of several cell types during vertebrate development.

Animals↗
PubMed2003

Mitotic G2-arrest is required for neural cell fate determination in Drosophila.

In the wing discs of Drosophila, the mecanosensory precursor cells are singled out from clusters of cells blocked at the G2 phase of the cell cycle. This mitotic quiescence and the selection of the precursors are under strict spatio-temporal control. We forced G2 cells to enter mitosis by overexpression of string, the Drosophila homologue of the cdc25 gene. Premature entrance in the cell cycle is associated to a loss of precursor cells. Precursors are lost consecutively to a transcriptional down-regulation of the determinant proneural achaete/scute genes. This down-regulation results from an over-activation of the Enhancer of Split genes, known as effectors of the Notch signalling pathway. We conclude that exit from the cell cycle is required for proper neural cell fate determination.

Animals↗
PubMed1997

Overexpression of a zebrafish homologue of the Drosophila neurogenic gene Delta perturbs differentiation of primary neurons and somite development.

We describe here the isolation and characterization of a zebrafish Delta homologue (delta D). A PCR fragment was used to obtain overlapping cDNA clones encoding a protein of 717 amino acids with all characteristic features of proteins of this family, a signal peptide, a transmembrane domain, and an extracellular region comprising the DSL domain and eight EGF-like repeats. The gene is transcribed in a complex pattern in the developing nervous system as well as in the hypoblast. Overexpression of this gene following mRNA injections leads to a reduction in the number of islet-I positive cells, which are assumed to be primary neurons, and to various defects in the adaxial mesoderm, as well as in the somites and myotomes. This suggests that delta D, and the Notch signalling pathway are involved in the differentiation of primary neurons within the neural plate, as well as in somite development.

Amino Acid Sequence↗
PubMed2000

The expression pattern of a novel Deltex homologue during chicken embryogenesis.

We isolated a partial cDNA encoding a novel chicken homologue of human Deltex (DTX1), a member of the Notch signaling pathway. The cDtx2 sequence showed higher homology to KIAA0937 protein (92% identical) than to DTX1 (68% identical). cDtx2 is expressed widely in the epiblast at stage 4. Later in development it is expressed in many neural and sensory structures, such as neural tube, migrating neural crest cells, epidermal placodes, cranial ganglia, and the optic and otic vesicles.

Amino Acid Sequence↗
PubMed2000

Transcriptional control of T cell development.

Transcriptional control of T cell development is a complex and rapidly moving area of investigation. Recent advances reveal critical roles for several transcription factors in T cell commitment, differentiation and selection. In particular, new roles for E proteins as well as members of the Notch signaling pathway have been described. Additionally, a unique function of Ikaros in chromatin remodeling reveals a novel mechanism by which transcriptional control may be exerted.

Cell Death↗
PubMed2000

Delta-like and gtl2 are reciprocally expressed, differentially methylated linked imprinted genes on mouse chromosome 12.

The distal portion of mouse chromosome 12 is imprinted. To date, however, Gtl2 is the only imprinted gene identified on chromosome 12. Gtl2 encodes multiple alternatively spliced transcripts with no apparent open reading frame. Using conceptuses with maternal or paternal uniparental disomy for chromosome 12 (UPD12), we found that Gtl2 is expressed from the maternal allele and methylated at the 5' end of the silent paternal allele. A reciprocally imprinted gene, Delta-like (Dlk), with homology to genes involved in the Notch signalling pathway was identified 80kb upstream of Gtl2. Dlk was expressed exclusively from the paternal allele in both the embryo and placenta, but the CpG-island promoter of Dlk was completely unmethylated on both parental alleles. Rather, a paternally methylated region was identified in the last exon of the active Dlk allele. The proximity, reciprocal imprinting and methylation in this domain are reminiscent of the co-ordinately regulated Igf2-H19 imprinted domain on mouse chromosome 7. Like H19 and Igf2, Gtl2 and Dlk were found to be co-expressed in the same tissues throughout development, though not after birth. These results have implications for the regulation, function and evolution of imprinted domains.

Alleles↗