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Results for “Receptor, Notch2”

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PubMed2006

Variable recombination efficiency in responder transgenes activated by Cre recombinase in the vasculature.

Cre recombinase has become a ubiquitous tool in transgenic strategies for regulation of transgene expression in a tissue-specific manner. We report analysis of two SM22alphaCre lines and their ability to mediate genomic recombination in five independent Cre-responsive transgenic lines. One of the SM22alphaCre lines developed was a tet-on system based on the reverse tetracycline transactivator. Our goal was to use this strategy to inhibit the Notch signaling pathway specifically in smooth muscle cells. Our responder transgenes contained a constitutively expressed marker gene (chloramphenicol acetyltransferase, CAT), flanked by loxP sites in direct orientation, upstream of Notch-related transgenes. We developed two dominant negative Notch transgenic responder lines activated by Cre-mediated DNA recombination. The first is the extracellular domain of human Jagged1, and the second is the extracellular domain of the human Notch2 receptor. Despite high expression of the marker gene in all responder lines, we found that Cre-mediated genomic recombination between these five lines was highly variable, ranging from 46 to 93% of individuals using an SM22alphaCre activating strain, or 8-58% of individuals using an inducible SM22alphartTACre. In all cases examined, detection of recombination by PCR correlated with expression of the transgene as determined by Western blot analysis. Our studies reflect the variability in recombination success based on the responder strain, presumably due to inaccessibility of the locus of integration of the responder allele.

Animals↗

PubMed2005

Effect of experimental varicocele on the expressions of Notch 1, 2, and 3 in rat testes: an immunohistochemical study.

OBJECTIVE: To study expressions of Notch receptor isoforms (Notch 1, 2, and 3) in normal and varicocele-induced rat testes to examine their possible functions in cell fate. DESIGN: Comparative and controlled study. SETTING: Animal Care and Operation Unit, Akdeniz University. ANIMAL(S): Wistar male rats for experimental and control groups. INTERVENTION(S): The control group underwent a sham operation (n = 6). The experimental groups underwent partial ligation of the renal vein to induce an experimental varicocele and then were killed 9 (n = 6), 11 (n = 6), and 13 (n = 6) weeks after the induction of varicocele. MAIN OUTCOME MEASURE(S): All tissues were fixed and routinely processed for paraffin embedding. Subsequent immunohistochemical studies were performed. RESULT(S): In the sham-operation rat testes, Leydig cells and elongated spermatids were immunopositive for Notch 1. Notch-2 expression was present in Leydig cells, spermatogonia, and primary spermatocytes. Notch-3 expression was limited to Leydig cells. Varicocele formation diminished the expression of both Notch-1 and Notch-2 receptors as the varicocele formation progressed over time. CONCLUSION(S): The present study suggests that Notch 1 is related to the maturation of spermatids. Notch 2 is related to both proliferation and maturation of spermatogenic cells, whereas Notch 3 seems to be related to Leydig cell functions. The decrease of both Notch-1 and Notch-2 expression depended on the degree of varicocele development over time, indicating a potential role in varicocele-associated testicular dysfunction.

Animals↗

PubMed2005

Evidence of marginal-zone B cell-positive selection in spleen.

Antigen receptor-mediated signaling is critical for the development and survival of B cells. However, it has not been established whether B cell development requires a signal from self-ligand engagement at the immature stage, a process known as "positive selection." Here, using a monoclonal B cell receptor (BCR) mouse line, specific for the self-Thy-1/CD90 glycoprotein, we demonstrate that BCR crosslinking by low-dose self-antigen promotes survival of immature B cells in culture. In spleen, an increase in BCR signaling strength, induced by low-dose self-antigen, directed naive immature B cells to mature, not into the default follicular B cell fate, but instead into the marginal-zone B cell subset. These data indicate that positive selection can occur in developing B cells and that BCR signal strength is a key factor in deciding between two functionally distinct mature B cell compartments in the microenvironment of the spleen.

Animals↗

PubMed2005

Cell type-specific and sexually dimorphic expression of transcription factor AP-2 in the adult mouse brain.

Expression of transcription factor AP-2 family genes in adult mouse brain regions was examined at RNA and protein levels and in tissue sections. AP-2 family RNA transcripts, nuclear AP-2 DNA binding activity, and AP-2 immunoreactivity were greatest in hindbrain and midbrain regions. Cells expressing AP-2 were predominantly differentiated neurons and were abundant in the solitary tract nucleus, hypoglossal nucleus, locus coeruleus, cerebellar molecular layer, superior colliculus, mitral cell layers of the main and accessory olfactory bulbs, and in some divisions of the bed nucleus of the stria terminalis. Sexually dimorphic expression of AP-2 was seen in the bed nucleus of the stria terminalis, a forebrain region required for regulation of gender-specific reproductive and social behaviors. In males, AP-2 expressing neurons were present in supracapsular, lateral ventral, and medial ventral divisions of the bed nucleus of the stria terminalis. In contrast, females had AP-2 expressing neurons in the lateral ventral division, but not the supracapsular division, and AP-2 expression in medial ventral division neurons oscillated during the estrus cycle. With the exception of the bed nucleus of the stria terminalis, forebrain regions generally lacked cells with high levels of AP-2. However, a small population of cells co-expressing low levels of AP-2 and Notch1 was sparsely distributed in the cerebral cortex and hippocampal dentate gyrus subgranular zone. Based on their variable levels of NeuN, a marker for differentiated neurons, these cells may include nascent neurons. A subset of cerebellar Purkinje cells also co-expressed low levels of AP-2 and Notch1. Together, the adult brain regions with AP-2 expressing neurons are notable for their importance in pathways that integrate sensory and neuroendocrine information for regulation of reproductive, social, and feeding behaviors. Our data suggest that AP-2 transcription factors contribute at multiple levels to adult brain function including regulation of gender-specific behavior.

Animals↗

PubMed2005

Notch1 and 2 cooperate in limb ectoderm to receive an early Jagged2 signal regulating interdigital apoptosis.

Spontaneous and engineered mutations in the Notch ligand Jagged2 produced the Syndactylism phenotype (Jiang, R.L., Lan, Y., Chapman, H.D., Shawber, C., Norton, C.R., Serreze, D.V., Weinmaster, G., Gridley, T., 1998. Defects in limb, craniofacial, and thymic Development in Jagged2 mutant mice. Genes Dev. 12, 1046-1057; Sidow, A., Bulotsky, M.S., Kerrebrock, A.W., Bronson, R.T., Daly, M.J., Reeve, M.P., Hawkins, T.L., Birren, B.W., Jaenisch, R., Lander, E.S., 1997. Serrate2 is disrupted in the mouse limb-development mutant syndactylism. Nature 389, 722-725). Given that additional ligands may be expressed in the developing limb bud, it was possible that loss of Jagged2 disabled only part of Notch function in the limb. In addition, it is not clear from the expression pattern of Jagged2 in the apical ectodermal ridge (AER) whether the ectodermal or mesenchymal compartment of the limb bud receives the Jagged2 signal. To elucidate the requirement for the Notch pathway in limb development, we have analyzed single and compound Notch receptor mutants as well as gamma-secretase-deficient limbs. Floxed alleles were removed either from the developing limb bud ectoderm (using Msx2-Cre) or from the mesenchyme (using Prx1-Cre). Our results confirm that Jagged2 loss describes the contribution of the entire Notch pathway to the mouse limb development and revealed that both Notch1 and 2 are required in the ectoderm to receive the Jagged2 signal. Interestingly, our allelic series allowed us to determine that Notch receives this signal at an early stage in the developmental process and that memory of this event is retained by the mesenchyme, where Notch signaling appears to be dispensable. Thus, Notch signaling plays a non-autonomous role in digit septation.

Animals↗

PubMed1997

Intracellular cleavage of Notch leads to a heterodimeric receptor on the plasma membrane.

Previous models for signal transduction via the Notch pathway have depicted the full-length Notch receptor expressed at the cell surface. We present evidence demonstrating that the Notch receptor on the plasma membrane is cleaved. This cleavage is an evolutionarily conserved, general property of Notch and occurs in the trans-Golgi network as the receptor traffics toward the plasma membrane. Although full-length Notch is detectable in the cell, it does not reach the surface. Cleavage results in a C-terminal fragment, N(TM), that appears to be cleaved N-terminal to the transmembrane domain, and an N-terminal fragment, N(EC), that contains most of the extracellular region. We provide evidence that these fragments are tethered together on the plasma membrane by a link that is sensitive to reducing conditions, forming a heterodimeric receptor.

Blotting, Western↗

PubMed2001

Notch receptors and hematopoiesis.

Notch receptors are involved in a variety of cell-fate decisions that affect the development and function of many organs, including hematopoiesis and the immune system. There are four mammalian Notch receptors that have only partially overlapping functions despite sharing similar structures and ligands. The ligands for Notch are transmembrane proteins expressed on adjacent cells, including Jagged and Delta, and it is quite possible that signaling is bidirectional. A large Notch precursor protein is proteolytically cleaved to form the mature cell-surface receptor. Ligand binding induces additional proteolytic events followed by translocation of the intracellular domain to the nucleus. There, Notch interacts with transcription factors such as RBPJ kappa, activating transcription of basic helix-loop-helix genes such as HES1. These in turn regulate expression of tissue-specific transcription factors that influence lineage commitment and other events. In this review, the details of Notch signaling will be discussed, with a focus on what is known about the role of Notch in hematopoiesis.

Animals↗

PubMed2004

Distribution pattern of Notch3 mutations suggests a gain-of-function mechanism for CADASIL.

Mutations in Notch3 cause the syndrome CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy). The mechanism by which these mutations result in a CADASIL phenotype has been widely speculated upon. A first step toward understanding a disease mechanism is to learn whether the mutations result in the loss of Notch3 function, in particular, its role in signaling or in the gain of a novel function. Notch3 genomic sequences were analyzed for sites of conservation across species. We present here a bioinformatic analysis of the Notch paralogs and orthologs that suggest that CADASIL mutations result in a gain of function. This finding diminishes the likelihood that a Notch3 signaling deficit is responsible for the phenotype and increases the likelihood that CADASIL joins the growing list of neurological diseases with protein deposits due to misfolding and aggregation.

Animals↗

PubMed2000

Notch gene expression during pancreatic organogenesis.

Notch receptors are involved in regulating the balance between cell differentiation and stem cell proliferation during the development of numerous tissues (Artavanis-Tsakonas, S., Matsuno, K., Fortini, M. E., 1995. Notch signaling. Science 268, 225-232). Here the expression of all four vertebrate Notch genes, their ligands, and some down-stream targets is analyzed during mouse pancreatic organogenesis. Notch 1 is the first Notch gene expressed in the pancreatic epithelium, and coexpression with HES 1 suggests that the Notch 1 pathway is activated. Notch 2 expression follows later when pancreatic buds branch and is restricted to embryonic ducts, believed to be the source for endocrine and exocrine stem cells. Notch 3 and Notch 4 are expressed in pancreatic mesenchyme and later in endothelial cells. Together these descriptive data comprise a framework for understanding the cellular basis for Notch function during pancreatic development.

Animals↗

PubMed2001

Dynamic expression patterns of the pudgy/spondylocostal dysostosis gene Dll3 in the developing nervous system.

Defects in the Notch pathway ligand Dll3 have been identified in the mouse pudgy (Dll3(pu)) and human spondylocostal dysostosis (SD, MIM 277300) mutations. Although these mutations are primarily associated with segmental defects in the axial skeleton and somitic patterning, they also exhibit cranial neurological defects. Therefore we have looked at the expression of Dll3 in the developing mouse nervous system. The expression of Notch ligands and receptors shares common features at 10.75 dpc in the rhombic lips and dorsal hindbrain. Temporal analysis of Dll3 expression from 9.0 to 11.0 dpc reveals that it is strongly expressed in laminar columns linked with regions of neuronal differentiation and hindbrain segmentation. Transverse sections show that Dll3 is expressed in territories where commissural neurons are formed. We have also looked at neuronal patterning in the mid-hindbrain region in Dll3(pu) mutants.

Animals↗

PubMed2001

Expression of Deltex1 during mouse embryogenesis: comparison with Notch1, 2 and 3 expression.

The Notch signalling pathway defines a phylogenetically conserved cell-cell communication process that enables cell-fate specification in multicellular organisms. Deltex is a component of the Notch signalling network that physically interacts with the ankyrin repeats of Notch. Here, we report on the expression pattern of the Deltex1 gene during mouse embryonic development and, furthermore, we compare its expression with that of the Notch1, 2 and 3 genes. Complementary and combinatorial expression patterns between Deltex1 and the three Notch genes were observed throughout embryogenesis since Deltex1 expression was related either to cytodifferentiation (i.e. neuronal tissues) or to cell proliferation events (i.e. eye, vascular structures, hematopoiesis).

Animals↗

PubMed2002

Expression of Notch genes and their ligands during gastrulation in the chicken embryo.

Notch signalling is an important evolutionary conserved mechanism known to control cell fate choices through local interactions. Here, the patterns of expression of Notch-1 and -2 genes and their ligands Delta-1, Serrate-1 and -2, were established in the early blastodisc of the chicken embryo from the pre-streak to the first somite stages. Delta-1 was detected as early as the pre-streak stage in the posterior part of the embryo shortly followed in the same region by Notch-1 at the initial streak stage. Thereafter both were strongly expressed in the posterior part of the primitive streak until HH4. Notch-2 was also found at the level of the streak although at low levels. Notch-1 was homogeneously expressed by the epiblast and by mesodermal cells ingressing at the level of the streak whereas Delta-1 expression formed a 'salt and pepper' pattern. The difference between the two was clearly detected by double in situ hybridisation. From the mid-streak to the first somite stages, Notch-1 and Delta-1 expressions appeared in the anterior part of the embryo. Serrate-1 and -2 were not detected at these stages. Taken together, these results constitute a framework for analysing the role(s) for Notch signalling during gastrulation.

Animals↗

PubMed2000

Notch signaling in T cell development.

Notch signaling regulates cell fate decisions during development. Recent experiments suggest that Notch signaling is essential for initial commitment to the T cell lineage and may function together with signals from the pre-TCR and the TCR to regulate subsequent steps of T cell development.

Animals↗

PubMed2003

Expression of Notch pathway genes in the embryonic mouse metanephros suggests a role in proximal tubule development.

The interaction of neighboring cells via Notch signalling leads to cell fate determination, differentiation and patterning of highly organized tissues. Mice with targeted disruption of genes from the Notch signal transduction pathway display defects in the developing somites, neurogenic structures, blood vessels, heart and other organs. Recent studies have added requirements for Notch signalling during kidney, pancreas and thymus morphogenesis. Here, we describe the expression of all four receptors (Notch1-4), the five transmembrane ligands (Dll1, 3, 4, Jag1 and Jag2), intracellular effectors (the Hey genes) and extracellular modulators (Lfng, Mfng, Rfng) in the developing mouse metanephros. Our results point to a Lfng-dependent role for Notch signalling in the development of nephron segments, especially the proximal tubules.

Animals↗

PubMed2004

Effects of indole fatty alcohols on the differentiation of neural stem cell derived neurospheres.

In a search for inducers of neuronal differentiation to treat neurodegenerative diseases such as Alzheimer's disease, a series of indole fatty alcohols (IFAs) were prepared. 13c (n = 18) was able to promote the differentiation of neural stem cell derived neurospheres into neurons at a concentration of 10 nM. Analysis of the expression of the Notch pathway genes in neurospheres treated during the differentiation phase with 13c (n = 18) revealed a significant decrease in the transcription of the Notch 4 receptor.

Alcohols↗

PubMed2005

Notch 2-positive progenitors with the intrinsic ability to give rise to pancreatic ductal cells.

Pancreatic adenocarcinomas display foci of duct-like structures that are positive for markers of pancreatic ductal cells. The development of these tumors is promoted by conditions leading to acinar-to-ductal metaplasia, a process by which acinar cells are replaced by ductal cells. Acinar-to-ductal metaplasia has recently been shown to proceed through intermediary cells expressing Nestin. To create an in vitro system to study pancreatic adenocarcinomas, we had used an hTERT cDNA to immortalize primary cells of the human pancreas. In this report, we show that the immortalized cells, termed hTERT-HPNE cells, have the ability to differentiate to pancreatic ductal cells. Exposing hTERT-HPNE cells to sodium butyrate and 5-aza-2'-deoxycytidine lead to the formation of pancreatic ductal cells marked by the expression of MDR-1, carbonic anhydrase II, and the cytokeratins 7, 8, and 19. hTERT-HPNE cells were found to have properties of the intermediary cells formed during acinar-to-ductal metaplasia, which included their undifferentiated phenotype, expression of Nestin, evidence of active Notch signaling, and ability to differentiate to pancreatic ductal cells. These results provide further evidence for the presence in the adult pancreas of a precursor of ductal cells. hTERT-HPNE cells should provide a useful model to study acinar-to-ductal metaplasia and the role played by this process in pancreatic cancer development.

Adenocarcinoma↗

PubMed2006

Evidence for differential expression of Notch receptors and their ligands in melanocytic nevi and cutaneous malignant melanoma.

The Notch signaling has been implicated in the regulation of self-renewal of adult stem cells and differentiation of precursors along a specific cell lineage, in normal embryonic development and organogenesis. There is also evidence that signaling through Notch receptors regulate cell proliferation and cell survival in several types of cancer, with opposing results depending on tissue context. No data are available in the literature concerning modulation of the expression of Notch receptors, and their ligands, in human cutaneous malignant melanoma. Here, we have investigated, for the first time, the expression of Notch-1, Notch-2, Jagged-1, Jagged-2 and Delta-like 1 proteins, by immunohistochemistry, in a series of benign and malignant human melanocytic lesions: five common melanocytic nevi, five 'dysplastic nevi' and 20 melanomas (five in situ, five T1-T2, five T3-T4 and five metastatic melanomas). We found that the expression of Notch-1 and Notch-2, as well as Notch ligands, was upregulated in 'dysplastic nevi' and melanomas as compared with common melanocytic nevi. These results indicate that the activation of Notch may represent an early event in melanocytic tumor growth and upregulation of Notch signaling may sustain tumor progression.

Adult↗

PubMed2002

Jagged-1 mediated activation of notch signaling induces complete maturation of human keratinocytes through NF-kappaB and PPARgamma.

Establishing an effective epidermal barrier requires a series of coordinated molecular events involving keratinocytes (KCs) within a stratified epithelium. Epidermal maturation depends on convergence of pathways involving components of NF-kappaB and peroxisome proliferator activated receptor (PPAR) signaling systems that promote terminal differentiation and production of a stratum corneum. The Notch-1 receptor and its ligand Delta-1 have been proposed by others to participate in early events in KC differentiation. Here, we establish differential expression patterns for several Notch receptors and ligands in normal human skin. These immunolocalization findings, together with functional studies demonstrating increased levels of Notch ligand/receptors occurring during the onset of differentiation, prompted use of a soluble Notch ligand, a peptide derived from the most conspicuously expressed ligand in skin, Jagged-1. Exposing submerged KC monolayers to this peptide (JAG-1) in co-presence of elevated calcium ion concentration, produced stratification with loricrin expression. Using a living human epidermal equivalent (EE) model system, when submerged cultures were raised to an air/liquid interface to generate a fully mature epidermis, activation of Notch signaling was detected. Addition of JAG-1 peptide to submerged EEs was sufficient to induce epidermal maturation. Moreover, a soluble decoy Notch inhibitor prevented such differentiation and corneogenesis in human EEs exposed to either an air/liquid interface or to the JAG-1 peptide. In KC monolayers, addition of JAG-1 peptide induced IKKalpha mediated NF-kappaB activation, as well as increased PPARgamma expression. Immunoprecipitation/Western blot analysis revealed a physical association between the p65 subunit of NF-kappaB and PPARgamma. These results indicate that activation of Notch signaling is necessary for maturation of human epidermis, and activation by a soluble Notch ligand is sufficient to trigger complete KC differentiation including cornification.

Adult↗