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PubMed2002

Presenilin-dependent gamma-secretase activity modulates neurite outgrowth.

Demonstration that cleavage of both APP and Notch are dependent on the product of the early onset Alzheimer's disease gene, presenilin-1 (PS1), has raised the possibility that Notch function may be altered in AD. This finding also suggests that Notch may be affected by APPgamma-secretase inhibitors under development for the treatment of Alzheimer's disease, as these target PS1. Data that address these questions have been lacking, due to inability to specifically modulate PS1 activity in a system directly relevant to the adult human brain. Using novel highly specific inhibitors of PS1/gamma-secretase, we demonstrate that modulation of PS1 activity in human CNS neurons not only affects Abeta generation, but also has unanticipated effects on Notch and its activity. We demonstrate that intracellular trafficking of Notch in human CNS neurons is altered by inhibition of PS1 and is accompanied by dramatic changes in neurite morphology, consistent with inhibition of Notch activity. These data, together with immunohistochemical evidence of elevation of Notch pathway expression in AD brain, suggest that Notch dysregulation may contribute to the neuritic dystrophy characteristically seen in Alzheimer's disease brain. In addition, they raise the possibility that inhibition of gamma-secretase/PS1 may have clinically beneficial effects on the neuritic pathology of AD, in addition to its expected effect to reduce amyloid burden.

Adaptor Proteins, Signal Transducing↗
PubMed2002

The soluble Notch ligand, Jagged-1, inhibits proliferation of CD34+ macrophage progenitors.

The Notch/Notch ligand system controls diverse cellular processes. The proteolytic cleavage generates transmembrane and soluble forms of Notch ligands. We examined the effect of a soluble Notch ligand, human Jagged-1, on human cord blood (CB) CD34+ cells, under serum-deprived conditions, using soluble human Jagged-1-immunoglobulin G1 chimera protein (hJagged-1). Soluble hJagged-1 inhibited myeloid colony formation but not erythroid-mix or erythroid colony formation, in the presence of stem cell factor (SCF), interleukin-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), G-CSF, thrombopoietin, and erythropoietin. Cytological analysis revealed that the decrease in myeloid colonies resulted mainly from the inhibition of macrophage colony formation. Furthermore, soluble hJagged-1 led to the inhibition of macrophage colony formation supported by M-CSF plus SCF and GM-CSF plus SCF. Delayed-addition experiments and the analysis of colony sizes demonstrated that soluble hJagged-l inhibited the growth of macrophage progenitors by acting in the early stage of macrophage development. The direct action of hJagged-1 was confirmed by the enhanced expression of the HES-1 (hairy enhancer of the split-1) gene. These results suggest that soluble hJagged-1 may regulate human hematopoiesis in the monocyte/macrophage lineage.

Antigens, CD↗
PubMed2002

Remodelling of the S3 PA700 proteasome activator gene chromatin structure during thymocyte differentiation.

The proteasome is the major cytosolic protease, composed of a 20S catalytic core that associates with either the 19S (PA700) activator or the 11S (PA28) regulator complex. The 19S complex is thought to promote protein substrate unfolding and subsequent degradation, but precise functions for the individual subunits remain undefined. The chromatin structure and regulation of the S3 (P91A) subunit of the 19S activator was examined as a novel approach towards understanding its role in the complex. DNase I hypersensitivity (HS) analysis of S3 chromatin revealed a ubiquitous DNase I HS site mapping to the promoter region. Examination of the S3 chromatin structure in thymocytes, a dynamic population that undergo substantial proliferation, apoptosis, and differentiation, revealed an additional DNase I HS site mapping to the sixth intron of the genomic sequence. This second site was demonstrated to be associated with CD4(+)CD8(+) double-positive (DP) but not CD4(+) single-positive (SP) thymoma cell lines, and may correlate with a downregulation of S3 message. When a DP thymic cell line was induced to differentiate through retroviral transduction with Notch-1, the second DNase I HS site was dramatically diminished, illustrating that S3 chromatin is developmentally regulated during thymocyte positive selection.

Animals↗
PubMed2005

Molecular and cell biological properties of mouse osteogenic mesenchymal progenitor cells, Kusa.

A cell line of murine osteogenic progenitor cells, Kusa, was established from femoral bone marrow stromal cells with other types of mesenchymal progenitor cells. We characterized two sublines of Kusa (Kusa-A1 and Kusa-O) from several aspects, including the use of an expression profiling system, a cDNA microarray. The original Kusa subline (Kusa-A1) had high alkaline phosphatase activity and high accumulation of calcium deposits in a condition inducing mineralization, with ascorbic acid and beta-glycerophosphate. Kusa-O, a low osteogenic subline of Kusa, had high alkaline phosphatase activity but slow accumulation of calcium deposits even in the inducing condition. These two Kusa sublines differed in the expression of the osteogenic marker genes, osteocalcin and osteopontin, during mineralization. A type of cDNA microarray revealed marked downregulation of gene expression in the inducing condition in both Kusa-A1 and Kusa-O. Another type of high-throughput microarray was performed to examine the difference in gene expression patterns between Kusa-A1 and Kusa-O. By this analysis, periostin, which would be involved in a stage of osteogenesis, was low in Kusa-A1. On the contrary, Myocyte enhancer factor 2C (MEF2C), a myogenic transcriptional factor, was high in Kusa-A1, although no expression of any other myogenic genes was shown.

Alkaline Phosphatase↗
PubMed1991

TAN-1, the human homolog of the Drosophila notch gene, is broken by chromosomal translocations in T lymphoblastic neoplasms.

Previously we described joining of DNA in the beta T cell receptor gene to DNA of an uncharacterized locus in a t(7;9)(q34;q34.3) chromosomal translocation from a case of human T lymphoblastic leukemia (T-ALL). We now show that the locus on chromosome 9 contains a gene highly homologous to the Drosophila gene Notch. Transcripts of the human gene, for which we propose the name TAN-1, and its murine counterpart are present in many normal human fetal and adult mouse tissues, but are most abundant in lymphoid tissues. In t(7;9)(q34;q34.3) translocations from three cases of T-ALL, the breakpoints occur within 100 bp of an intron in TAN-1, resulting in truncation of TAN-1 transcripts. These observations suggest that TAN-1 may be important for normal lymphocyte function and that alteration of TAN-1 may play a role in the pathogenesis of some T cell neoplasms.

Amino Acid Sequence↗
PubMed1995

Involvement of Notch-1 in mammalian retinal neurogenesis: association of Notch-1 activity with both immature and terminally differentiated cells.

The Notch pathway is thought to define an evolutionarily conserved signaling mechanism that regulates the differentiation of immature cells through cells interactions. We have examined the expression of the Notch-1 receptor, the central element of this pathway, in the developing rat retina, where cell-fate choices depend upon a series of local cell interactions. Notch-1 immunoreactivity is associated with differentiating cells at different stages of retinal neurogenesis, suggesting that Notch-1 may play a role in the successive cell-fate determination which governs retinal development. In addition, the Notch-1 immunoreactivity is detected in nuclei of postmitotic, differentiated neurons of the adult retina. Our observations raise the possibility that besides its role in the differentiation of immature cell populations Notch-1 activity may also be involved in the maintenance of the differentiated state.

Amino Acid Sequence↗
PubMed2006

Jagged1 protein enhances the differentiation of mesenchymal stem cells into cardiomyocytes.

BACKGROUND: Mesenchymal stem cells (MSCs) can differentiate into cardiomyocytes if an appropriate cellular environment is provided. Notch signals exchanged between neighboring cells through the Notch receptor can eventually dictate cell differentiation. In our study, we show that MSC differentiation into cardiomyocytes is dependent on the Notch signal. METHODS: We created a myocardial infarction model in rat by coronary ligation, administered direct intramyocardial injection of DAPI-labeled MSC immediately, and observed the differentiation of MSCs after 14 days by immunofluorescence staining against troponin T. We cultured MSCs and cardiomyocytes in four ways, respectively, in vitro. (1) MSCs cocultured with cardiomyocytes obtained from neonatal rat ventricles in a ratio of 1:10. (2) The two types of cells were cultured in two chambers separated by a semipermeable membrane as indirect coculture group. (3) Notch receptor-soluble jagged1 protein was added to indirect coculture group. (4) Both jagged1 protein and gamma-secretase inhibitor-DAPT were added to indirect coculture group. Two weeks later, we observed the differentiation percentage, respectively, by immunofluorescence staining. RESULTS: We found the differentiation of MSCs which were close to cardiomyocytes in vivo. The differentiation percentage of the four cell culture group was 30.13+/-2.16%, 12.52+/-1.18%, 26.33+/-2.20%, and 13.08+/-1.15%. CONCLUSIONS: MSCs can differentiate into cardiomyocytes in vitro and in vivo if a cardiomyocyte microenvironment is provided. 2. Cell-to-cell interaction is very important for the differentiation of MSCs into cardiomyocytes. 3. Jagged1 protein can activate Notch signal and enhance the differentiation of MSC into cardiomyocyte, while the effect can be inhibited by DAPT.

Animals↗
PubMed2004

Characterization of tissue specific expression of Notch-1 in human tissues.

Signaling through the Notch cell surface receptors is a highly conserved mechanism of cell fate specification. Notch signaling regulates proliferation, differentiation and cell death. In vertebrates, putative gene duplication has originated four Notch genes, Notch-1, -2, -3 and -4. They have been implicated in neurogenesis, hematopoiesis, T-cell development, vasculogenesis and brain cortical growth. We have investigated Notch-1 distribution in normal human tissues by immunohistochemistry and immunoblot. We detected widespread expression of Notch-1 cytoplasmatic staining, with different tissue distributions in the different organs examined. In particular, high expression of Notch-1 was detected in the intermediate suprabasal layers, but not in the dead cells at the extreme periphery of stratified epithelia. Moreover, a low/intermediate level of Notch-1 was observed in lymphocytes in several peripheral lymphoid tissues; in particular the germinal centers of lymph nodes showed the most abundant number of positive cells, which appeared to be centroblasts/immunoblasts based on nuclear morphology. Notch-1 participates in keratinocytes differentiation. We showed by Western blot analysis that Notch-1 level was clearly increased in HaCaT cells after Ca(++) addition and remained substantially elevated until late differentiation stages. These results suggest that Notch-1 may function in numerous cell types in processes beyond cell fate determination, such as neuronal plasticity, muscle hypertrophy, liver regeneration, and germinal center lymphopoiesis during the immune response.

Blotting, Western↗
PubMed2004

Notch signaling in T- and B-cell development.

The Notch family of evolutionarily conserved proteins regulates a broad spectrum of cell-fate decisions and differentiation processes during fetal and post-natal development. The best characterized role of Notch signaling during mammalian hematopoiesis and lymphopoiesis is the essential function of the Notch1 receptor in T-cell lineage commitment. More recent studies have addressed the roles of other Notch receptors and ligands, as well as their downstream targets, revealing additional novel functions of Notch signaling in intra-thymic T-cell development, B-cell development and peripheral T-cell function.

Animals↗
PubMed2005

Integration of Notch 1 and calcineurin/NFAT signaling pathways in keratinocyte growth and differentiation control.

The Notch and Calcineurin/NFAT pathways have both been implicated in control of keratinocyte differentiation. Induction of the p21(WAF1/Cip1) gene by Notch 1 activation in differentiating keratinocytes is associated with direct targeting of the RBP-Jkappa protein to the p21 promoter. We show here that Notch 1 activation functions also through a second Calcineurin-dependent mechanism acting on the p21 TATA box-proximal region. Increased Calcineurin/NFAT activity by Notch signaling involves downregulation of Calcipressin, an endogenous Calcineurin inhibitor, through a HES-1-dependent mechanism. Besides control of the p21 gene, Calcineurin contributes significantly to the transcriptional response of keratinocytes to Notch 1 activation, both in vitro and in vivo. In fact, deletion of the Calcineurin B1 gene in the skin results in a cyclic alopecia phenotype, associated with altered expression of Notch-responsive genes involved in hair follicle structure and/or adhesion to the surrounding mesenchyme. Thus, an important interconnection exists between Notch 1 and Calcineurin-NFAT pathways in keratinocyte growth/differentiation control.

Alopecia↗
PubMed2005

Hypoxia requires notch signaling to maintain the undifferentiated cell state.

In addition to controlling a switch to glycolytic metabolism and induction of erythropoiesis and angiogenesis, hypoxia promotes the undifferentiated cell state in various stem and precursor cell populations. Here, we show that the latter process requires Notch signaling. Hypoxia blocks neuronal and myogenic differentiation in a Notch-dependent manner. Hypoxia activates Notch-responsive promoters and increases expression of Notch direct downstream genes. The Notch intracellular domain interacts with HIF-1alpha, a global regulator of oxygen homeostasis, and HIF-1alpha is recruited to Notch-responsive promoters upon Notch activation under hypoxic conditions. Taken together, these data provide molecular insights into how reduced oxygen levels control the cellular differentiation status and demonstrate a role for Notch in this process.

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↗
PubMed2006

The potential involvement of Notch signaling in NK cell development.

NK cells constitute an essential element of the innate immune system; however, the cellular and molecular mechanisms that guide their early development are still poorly understood. Here, we demonstrate that in addition to its known crucial role in T cell development, Notch signaling can also be involved in NK cell development. Thus, upon co-culture on OP9 stroma expressing the Notch ligand Delta-like 1 (OP9-DL1), Pax5-deficient pro-B cells, which have multi-lineage potential, efficiently differentiate into T and NK cells. Upon DL-1 signaling, Pax5-deficient pro-B cells down-regulate both surface CD93 expression and transcripts for B cell-specific genes and concomitantly up-regulate T lineage gene transcripts. Subsequent transfer of DL-1-signaled Pax5-deficient pro-B cells onto OP9 stroma in the presence of IL-2 leads to their efficient differentiation into NK1.1(+), functional NK cells. Moreover, bone marrow early progenitor with lymphoid and myeloid differentiation potential (EPLM), which we have previously described as the normal in vivo-equivalent of Pax5-deficient pro-B cells, also gain the ability to differentiate into effector NK cells following transient DL1 Notch-mediated signaling. The potential involvement of Notch signaling in the generation of the NK cell repertoire in vivo is discussed.

Animals↗
PubMed2004

Cellular niches controlling B lymphocyte behavior within bone marrow during development.

In bone marrow, hematopoiesis is thought to depend on special microenvironments known as niches that maintain blood cells. However, the identity of niches and interaction of blood cells with niches remain poorly understood. Here we identify stage-specific cellular niches for B lymphopoiesis. The earliest precursors, pre-pro-B cells and end-stage B cells, plasma cells require CXC chemokine ligand (CXCL)12. CXCL12-expressing cells are a small population of stromal cells, scattered throughout bone marrow and located some distance from the cells expressing interleukin (IL)-7. Multipotent hematopoietic progenitors are attached to the processes of CXCL12-expressing cells and pre-pro-B cells adjoin their cell bodies. Maturer pro-B cells that require IL-7 have moved away and adjoin the IL-7-expressing cells. Plasma cells again seed CXCL12-expressing cells. We demonstrate the B lymphocyte characteristic location and movement between specific niches within bone marrow during development and suggest that CXCL12 maintains the cells in the niche.

Animals↗
PubMed2005

Isolation of precursor cells (PCs) from human dental follicle of wisdom teeth.

The dental follicle is an ectomesenchymal tissue surrounding the developing tooth germ. It is believed that this tissue contains stem cells and lineage committed progenitor cells or precursor cells (PCs) for cementoblasts, periodontal ligament cells, and osteoblasts. In this study, we report the isolation of PCs derived from dental follicle of human third molar teeth. These fibroblast-like, colony forming and plastic adherent cells expressed putative stem cell markers Notch-1 and Nestin. We compared gene expressions of PCs, human mesenchymal stem cells (hMSCs), periodontal ligament cells (PDL-cells) and osteoblasts (MG63) for delimitation of PCs. Interestingly, PCs expressed higher amounts of insulin-like growth factor-2 (IGF-2) transcripts than hMSCs. Differentiation capacity was demonstrated under in vitro conditions for PCs. Long-term cultures with dexamethasone produced compact calcified nodules or appeared as plain membrane structures of different dimensions consisting of a connective tissue like matrix encapsulated by a mesothelium-like cellular structure. PCs differentially express osteocalcin (OCN) and bone sialoprotein (BS) after transplantation in immunocompromised mice but without any sign of cementum or bone formation. Therefore, our results demonstrate that cultured PCs are unique undifferentiated lineage committed cells residing in the periodontium prior or during tooth eruption.

Adolescent↗
PubMed2005

Mind bomb1 is a ubiquitin ligase essential for mouse embryonic development and Notch signaling.

The Notch-Delta signaling pathway controls many conserved cell determination events. While the Notch end is fairly well characterized, the Delta end remains poorly understood. Mind bomb1 (MIB1) is one of two E3 ligases known to ubiquitinate Delta. We report here that a targeted mutation of Mib1 in mice results in embryonic lethality by E10.5. Mutants exhibit multiple defects due to their inability to modulate Notch signaling. As histopathology revealed a strong neurogenic phenotype, this study concentrates on characterizing the Mib1 mutant by analyzing Notch pathway components in embryonic neuroepithelium prior to developmental arrest. Premature neurons were observed to undergo apoptosis soon after differentiation. Aberrant neurogenesis is a direct consequence of lowered Hes1 and Hes5 expression resulting from the inability to generate Notch1 intracellular domain (NICD1). We conclude that MIB1 activity is required for S3 cleavage of the Notch1 receptor. These results have direct implications for manipulating the differentiation of neuronal stem cells and provide a putative target for the modulation of specific tumors.

Amino Acid Sequence↗
PubMed2004

Targeting promiscuous signaling pathways in cancer: another Notch in the bedpost.

The chromosomal translocation t(7;9)(q34;q34.3) in human T-cell acute lymphoblastic leukemia results in the constitutive activation of Notch (Nic). Reported mutations in Ikaros cause the loss of DNA-binding, which in turn leads to a loss of repressive activity. Recently, these two mutations have been shown to cooperate in leukemogenesis. The current model proposes that the combination of the loss of Ikaros activity and the gain of constitutive Notch activity disrupts the normal balance between repression and activation at common regulatory elements. Furthermore, the model is extended to suggest that multiple transcription factors coordinate transcriptional repression and activation through these common regulatory elements. In leukemogenesis, the breakdown of this coordinate regulation underlies one of the pathophysiological mechanisms. Finally, using Notch as a template, potential points of interdiction by designer therapeutics are discussed.

DNA-Binding Proteins↗