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Results for “Jagged-2 Protein”

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At least 19 recordsLinked to original sources
PubMed2000

Jagged2 induces cell cycling in confluent fibroblasts susceptible to density-dependent inhibition of cell division.

Jagged2 is a member of the DSL (Delta-Serrate-Lag-2) -ligand family of transmembrane proteins that signal through the Notch receptors. In many cases of human acute lymphoblastic T-cell leukemias, chromosomal translocations fuse a part of the Notch-1 gene to the T-cell receptor-beta locus (Ellison et al., 1991, Cell 66:649-661). The truncated Notch-1 allele encodes an aberrant protein that lacks most of the extracellular domain and is constitutively activated (Pear et al., 1996, J Exp Med 183:2283-2291). A similarly truncated version of Notch-1 was capable of transforming primary baby rat kidney cells in cooperation with the E1A oncogene of adenovirus (Capobianco et al., 1997, Mol Cell Bio 17:6265-6273). The transformed cells grew to a high population density in culture and were tumorigenic in vivo. It was unclear what roles Notch signaling played in neoplastic transformation. In this report, we demonstrate that sustained activation of the Jagged2/Notch signal transduction pathway induced continuous cell cycling in confluent rabbit-skin fibroblasts sensitive to density-dependent inhibition of cell division. The ability to overcome density-dependent inhibition of cell division correlated with elevated cyclin-dependent kinase-2 (CDK2) activity and a lower level of induction of the CDK inhibitor p27 in the target cells. Similar cell-cycle effect was seen when a truncated mouse Notch-1 construct with constitutive activity was expressed. Taken together, our findings indicate that sustained activation of the Jagged2/Notch signal transduction pathway can overcome density-dependent inhibition of cell division and therefore may contribute to neoplastic transformation.

Animals↗
PubMed1996

Jagged2: a serrate-like gene expressed during rat embryogenesis.

DSL (Delta, Serrate, Lag-2) ligands activate Notch signaling and thereby regulate the differentiation of many different cell types during development. We have isolated a novel Serrate-like gene, Jagged2, whose amino acid sequence and expression pattern during rat embryogenesis suggest that it functions as a ligand for Notch. In contrast to previously described DSL ligands for Notch, Jagged2 is not widely expressed in the developing central nervous system. However, Jagged2 and Notch1 are coexpressed in the apical ectodermal ridge (AER), suggesting a role for this ligand-receptor pair in limb development. Furthermore, unlike Jagged1, Jagged2 is coexpressed with Notch in the developing thymus, where it may induce Notch signaling to direct T-cell fate. Our data are consistent with the idea that the diversity of cell types regulated by Notch signaling is a consequence of activation of unique Notch isoforms by different DSL ligands.

Amino Acid Sequence↗
PubMed2000

Characterization, chromosomal localization, and the complete 30-kb DNA sequence of the human Jagged2 (JAG2) gene.

The genomic sequence of the human Jagged2 (JAG2) gene, which encodes a ligand for the Notch receptors, was determined. The 30-kb DNA sequence spanning the JAG2 gene contains 26 exons and a putative promoter region. Several potential binding sites for transcription factors, including NF-kappab, E47, E12, E2F, Ets-1, MyoD, and OCT-1, were found in the human JAG2 promoter region. The JAG2 gene was also mapped to the chromosomal region 14q32 using fluorescence in situ hybridization.

Base Sequence↗
PubMed1999

Phylogenetic analysis of vertebrate and invertebrate Delta/Serrate/LAG-2 (DSL) proteins.

Delta/Serrate/LAG-2 (DSL) proteins are putative transmembrane signaling molecules that regulate cell differentiation in metazoans. DSL proteins are characterized by the presence of a motif unique to these proteins, the DSL motif, and a variable number of tandemly repeated copies of an epidermal growth factor-like (EGF) motif. We have completed a phylogenetic analysis of 15 DSL proteins from eight species. Our findings reveal that at least one gene duplication occurred prior to the divergence of the Drosophila melanogaster and vertebrate lineages, with subsequent duplications in vertebrates. The three known Caenorhabditis elegans proteins likely arose by two independent duplications in the nematode lineage. Analysis of EGF repeats suggests that EGF 2 has been conserved among DSL proteins in vertebrates and D. melanogaster. The sequences of two EGF repeats have been perfectly conserved in vertebrate orthologs: EGF 2 in Delta and EGF 15 in Jagged/Serrate. Finally, the linear order of EGF repeats has been conserved in the vertebrate Jagged/Serrate orthologs and vertebrate Delta orthologs.

Amino Acid Sequence↗
PubMed1999

Human ligands of the Notch receptor.

During development, the Notch signaling pathway is essential for the appropriate differentiation of many cell types in organisms across the phylogenetic scale, including humans. Notch signaling is also implicated in human diseases, including a leukemia and two hereditary syndromes known as Alagille and CADASIL. To generate tools for pursuing the role of the Notch pathway in human disease and development, we have cloned and analyzed the expression of three human homologues of the Notch ligands Delta and Serrate, human Jagged1 (HJ1), human Jagged2 (HJ2), and human Delta1 (H-Delta-1), and determined their chromosomal localizations. We have also raised antibodies to HJ1, and used these antibodies in conjunction with in situ hybridization to examine the expression of these ligands in normal and cancerous cervical tissue. We find that, as reported previously for Notch, the ligands are up-regulated in certain neoplastic tissues. This observation is consistent with the notion that Notch signaling is an important element in these pathogenic conditions, raising the possibility that modulation of Notch activity could be used to influence the fate of the cells and offering a conceivable therapeutic avenue.

Amino Acid Sequence↗
PubMed1997

JAGGED2: a putative Notch ligand expressed in the apical ectodermal ridge and in sites of epithelial-mesenchymal interactions.

The Drosophila Notch gene and its ligands, Delta and Serrate, are involved in cell fate determination in a variety of developing tissues. Recently, several Notch, Delta and Serrate homologues have been identified in vertebrates. We report here the cloning of the human and murine JAGGED2 (JAG2), a Serrate-like gene, and the analysis of its expression pattern during embryogenesis. Jag2 was found to be expressed as early as E9 in the surface ectoderm of the branchial arches and in the apical ectodermal ridge (AER) of the developing limb. At E12.5, Jag2 expression is upregulated in differentiated neurons of the central and peripheral nervous system and in the inner neuroblastic layer of the developing retina. Outside the nervous system, Jag2 is expressed in the developing vibrissae follicles, tooth buds, thymus, submandibular gland and stomach. Our findings suggest the involvement of Jagged2 in the development of the mammalian limb, branchial arches, central and peripheral nervous systems and several tissues whose development depends upon epithelial-mesenchymal interactions.

Animals↗
PubMed1999

Notch signalling pathway mediates hair cell development in mammalian cochlea.

The mammalian cochlea contains an invariant mosaic of sensory hair cells and non-sensory supporting cells reminiscent of invertebrate structures such as the compound eye in Drosophila melanogaster. The sensory epithelium in the mammalian cochlea (the organ of Corti) contains four rows of mechanosensory hair cells: a single row of inner hair cells and three rows of outer hair cells. Each hair cell is separated from the next by an interceding supporting cell, forming an invariant and alternating mosaic that extends the length of the cochlear duct. Previous results suggest that determination of cell fates in the cochlear mosaic occurs via inhibitory interactions between adjacent progenitor cells (lateral inhibition). Cells populating the cochlear epithelium appear to constitute a developmental equivalence group in which developing hair cells suppress differentiation in their immediate neighbours through lateral inhibition. These interactions may be mediated through the Notch signalling pathway, a molecular mechanism that is involved in the determination of a variety of cell fates. Here we show that genes encoding the receptor protein Notch1 and its ligand, Jagged 2, are expressed in alternating cell types in the developing sensory epithelium. In addition, genetic deletion of Jag2 results in a significant increase in sensory hair cells, presumably as a result of a decrease in Notch activation. These results provide direct evidence for Notch-mediated lateral inhibition in a mammalian system and support a role for Notch in the development of the cochlear mosaic.

Animals↗
PubMed1999

Expression pattern of notch1, 2 and 3 and Jagged1 and 2 in lymphoid and stromal thymus components: distinct ligand-receptor interactions in intrathymic T cell development.

The suggested role of Notch1 or its mutants in thymocyte differentiation and T cell tumorigenesis raises the question of how the different members of the Notch family influence distinct steps in T cell development and the role played by Notch ligands in the thymus. We report here that different Notch receptor-ligand partnerships may occur inside the thymus, as we observed differential expression of Notch1, 2 and 3 receptors, their ligands Jagged1 and 2, and downstream intracellular effectors hairy and Enhancer of Split homolog 1 (HES-1) and hairy and Enhancer of Split homolog 5 (HES-5), depending on ontogenetic stage and thymic cell populations. Indeed, while Jagged2 is expressed in both stromal cells and thymocytes, Jagged1 expression is restricted to stromal cells. Moreover, a differential distribution of Notch3, with respect to Notch1, was observed in distinct age-related thymocyte subsets. Finally, Notch3 was preferentially up-regulated in thymocytes, following the induction of their differentiation by interaction with thymic epithelial cells expressing the cognate Jagged1 and 2 ligands, suggesting that, besides Notch1, Notch3 may also be involved in distinct steps of thymocyte development. Our results suggest that the Notch signaling pathway is involved in a complex interplay of T cell developmental stages, as a consequence of the heterogeneity and specific expression of members of the Notch receptor family and their cognate ligands, in distinct thymic cell compartments.

Animals↗
PubMed1997

Isolation and functional analysis of a cDNA for human Jagged2, a gene encoding a ligand for the Notch1 receptor.

Signaling through Notch receptors has been implicated in the control of cellular differentiation in animals ranging from nematodes to humans. Starting from a human expressed sequence tag-containing sequence resembling that of Serrate, the gene for a ligand of Drosophila melanogaster Notch, we assembled a full-length cDNA, now called human Jagged2, from overlapping cDNA clones. The full-length cDNA encodes a polypeptide having extensive sequence homology to Serrate (40.6% identity and 58.7% similarity) and even greater homology to several putative mammalian Notch ligands that have subsequently been described. When in situ hybridization was performed, expression of the murine Jagged2 homolog was found to be highest in fetal thymus, epidermis, foregut, dorsal root ganglia, and inner ear. In Northern blot analysis of RNA from tissues of 2-week-old mice, the 5.0-kb Jagged2 transcript was most abundant in heart, lung, thymus, skeletal muscle, brain, and testis. Immunohistochemistry revealed coexpression of Jagged2 and Notch1 within thymus and other fetal murine tissues, consistent with interaction of the two proteins in vivo. Coculture of fibroblasts expressing human Jagged2 with murine C2C12 myoblasts inhibited myogenic differentiation, accompanied by increased Notch1 and the appearance of a novel 115-kDa Notch1 fragment. Exposure of C2C12 cells to Jagged2 led to increased amounts of Notch mRNA as well as mRNAs for a second Notch receptor, Notch3, and a second Notch ligand, Jagged1. Constitutively active forms of Notchl in C2C12 cells also induced increased levels of the same set of mRNAs, suggesting positive feedback control of these genes initiated by binding of Jagged2 to Notch1. This feedback control may function in vivo to coordinate differentiation across certain groups of progenitor cells adopting identical cell fates.

Amino Acid Sequence↗
PubMed2000

Binding of Delta1, Jagged1, and Jagged2 to Notch2 rapidly induces cleavage, nuclear translocation, and hyperphosphorylation of Notch2.

Delta1, Jagged1, and Jagged2, commonly designated Delta/Serrate/LAG-2 (DSL) proteins, are known to be ligands for Notch1. However, it has been less understood whether they are ligands for Notch receptors other than Notch1. Meanwhile, ligand-induced cleavage and nuclear translocation of the Notch protein are considered to be fundamental for Notch signaling, yet direct observation of the behavior of the Notch molecule after ligand binding, including cleavage and nuclear translocation, has been lacking. In this report, we investigated these issues for Notch2. All of the three DSL proteins bound to endogenous Notch2 on the surface of BaF3 cells, although characteristics of Jagged2 for binding to Notch2 apparently differed from that of Delta1 and Jagged1. After binding, the three DSL proteins induced cleavage of the membrane-spanning subunit of Notch2 (Notch2(TM)), which occurred within 15 min. In a simultaneous time course, the cleaved fragment of Notch2(TM) was translocated into the nucleus. Interestingly, the cleaved Notch2 fragment was hyperphosphorylated also in a time-dependent manner. Finally, binding of DSL proteins to Notch2 also activated the transcription of reporter genes driven by the RBP-Jkappa-responsive promoter. Together, these data indicate that all of these DSL proteins function as ligands for Notch2. Moreover, the findings of rapid cleavage, nuclear translocation, and phosphorylation of Notch2 after ligand binding facilitate the understanding of the Notch signaling.

Animals↗
PubMed2000

Notch signaling regulates the pattern of auditory hair cell differentiation in mammals.

The development of the mammalian cochlea is an example of patterning in the peripheral nervous system. Sensory hair cells and supporting cells in the cochlea differentiate via regional and cell fate specification. The Notch signaling components shows both distinct and overlapping expression patterns of Notch1 receptor and its ligands Jagged1 (Jag1) and Jagged2 (Jag2) in the developing auditory epithelium of the rat. On embryonic day 16 (E16), many precursor cells within the Kölliker's organ immunostained for the presence of both Notch1 and Jag1, while the area of hair cell precursors did not express either Notch1 and Jag1. During initial events of hair cell differentiation between E18 and birth, Notch1 and Jag1 expression predominated in supporting cells and Jag2 in nascent hair cells. Early after birth, Jag2 expression decreased in hair cells while the pattern of Notch1 expression now included both supporting cells and hair cells. We show that the normal pattern of hair cell differentiation is disrupted by alteration of Notch signaling. A decrease of either Notch1 or Jag1 expression by antisense oligonucleotides in cultures of the developing sensory epithelium resulted in an increase in the number of hair cells. Our data suggest that the Notch1 signaling pathway is involved in a complex interplay between the consequences of different ligand-Notch1 combinations during cochlear morphogenesis and the phases of hair cell differentiation.

Animals↗
PubMed2000

Mouse Jagged2 is differentially expressed in hematopoietic progenitors and endothelial cells and promotes the survival and proliferation of hematopoietic progenitors by direct cell-to-cell contact.

To study the regulation of the early stages of hematopoiesis, cDNA representational difference analysis was used to isolate genes that were differentially expressed in primitive hematopoietic progenitors. The reasoning was that such genes were more likely to provide functions important to hematopoietic stem cells and progenitors. One of the genes identified through this approach encodes mouse Jagged2 (mJagged2). Using quantitative reverse transcription-polymerase chain reaction, it was shown that mJagged2 was differentially expressed in c-kit(+) hematopoietic progenitors, including those with the phenotypes of Lin(-) c-kit(+) Rh(lo) Ho(lo) and Lin(-) c-kit(+) Rh(hi) Ho(lo), and that they have been shown to be highly enriched for long-term and short-term repopulating hematopoietic stem cells, respectively. Western blot analyses showed that endothelial cells also expressed high levels of Jagged2, but stromal fibroblasts did not. Using a coculture system we found that exogenous, full-length mJagged2 promoted the survival and proliferation of hematopoietic progenitors, including the high-proliferative potential colony-forming cells. Direct cell-to-cell contact was required for this effect. Taken together, these findings indicate that both c-kit(+) hematopoietic progenitors and endothelial cells express Jagged2 and that exogenous, full-length Jagged2 promotes the survival and proliferation of hematopoietic progenitors.

Animals↗
PubMed1999

Notch1-induced delay of human hematopoietic progenitor cell differentiation is associated with altered cell cycle kinetics.

Hematopoiesis is a balance between proliferation and differentiation that may be modulated by environmental signals. Notch receptors and their ligands are highly conserved during evolution and have been shown to regulate cell fate decisions in multiple developmental systems. To assess whether Notch1 signaling may regulate human hematopoiesis to maintain cells in an immature state, we transduced a vesicular stomatitis virus G-protein (VSV-G) pseudo-typed bicistronic murine stem cell virus (MSCV)-based retroviral vector expressing a constitutively active form of Notch1 (ICN) and green fluorescence protein into the differentiation competent HL-60 cell line and primary cord blood-derived CD34(+) cells. In addition, we observed endogenous Notch1 expression on the surface of both HL-60 cells and primary CD34(+) cells, and therefore exposed cells to Notch ligand Jagged2, expressed on NIH3T3 cells. Both ligand-independent and ligand-dependent activation of Notch resulted in delayed acquisition of differentiation markers by HL-60 cells and cord blood CD34(+) cells. In addition, primary CD34(+) cells retained their ability to form immature colonies, colony-forming unit-mix (CFU-mix), whereas control cells lost this capacity. Activation of Notch1 correlated with a decrease in the fraction of HL-60 cells that were in G0/G1 phase before acquisition of a mature cell phenotype. This enhanced progression through G1 was noted despite preservation of the proliferative rate of the cells and the overall length of the cell cycle. These findings show that Notch1 activation delays human hematopoietic differentiation and suggest a link of Notch differentiation effects with altered cell cycle kinetics.

3T3 Cells↗
PubMed1998

Defects in limb, craniofacial, and thymic development in Jagged2 mutant mice.

The Notch signaling pathway is a conserved intercellular signaling mechanism that is essential for proper embryonic development in numerous metazoan organisms. We have examined the in vivo role of the Jagged2 (Jag2) gene, which encodes a ligand for the Notch family of transmembrane receptors, by making a targeted mutation that removes a domain of the Jagged2 protein required for receptor interaction. Mice homozygous for this deletion die perinatally because of defects in craniofacial morphogenesis. The mutant homozygotes exhibit cleft palate and fusion of the tongue with the palatal shelves. The mutant mice also exhibit syndactyly (digit fusions) of the fore- and hindlimbs. The apical ectodermal ridge (AER) of the limb buds of the mutant homozygotes is hyperplastic, and we observe an expanded domain of Fgf8 expression in the AER. In the foot plates of the mutant homozygotes, both Bmp2 and Bmp7 expression and apoptotic interdigital cell death are reduced. Mutant homozygotes also display defects in thymic development, exhibiting altered thymic morphology and impaired differentiation of gamma delta lineage T cells. These results demonstrate that Notch signaling mediated by Jag2 plays an essential role during limb, craniofacial, and thymic development in mice.

Animals↗
PubMedDate not supplied

Expression of proneural and neurogenic genes in the embryonic mammalian vestibular system.

One of the most striking aspects of all auditory and vestibular sensory epithelia is the mosaic pattern of hair cells and supporting cells. The factors that are required for the development of this mosaic have not been determined, however the results of recent studies have demonstrated that components of the neurogenic (Notch) signaling pathway are expressed in the developing inner ears of a number of different vertebrate species. To examine whether this signaling pathway may play a similar role in the development of the hair cell mosaic in the mammalian vestibular system, the expression patterns of proneural (Math1) and neurogenic (Notch1, Jagged2, HES5) genes were examined in the developing mouse inner ear. Results indicate that Notch1 is initially expressed throughout the developing inner ear and becomes restricted to non-sensory cells within the developing sensory epithelia. In contrast, initial expression of Math1 and Jagged2 is localized to the developing sensory epithelia and ultimately becomes restricted to hair cells. Interestingly, transcripts for HES5, a target of Notch activation, are expressed in the developing cristae but not in the saccule or utricle. These results are consistent with the hypothesis that formation of the hair cell mosaic is regulated through the neurogenic pathway. However the differential expression of HES5 within the ear indicates that the downstream targets of Notch1 activation are not consistent across all of the sensory epithelia and suggests that the effects of activation of Notch1 in the saccule and utricle must be regulated through alternate target genes.

Animals↗