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PubMed2006

Notch signaling in cancer.

The evolutionarily conserved developmental pathway driven by Notch receptors and ligands has acquired multiple post-natal homeostatic functions in vertebrates. Potential roles in human physiology and pathology are being studied by an increasingly large number of investigators. While the canonical Notch signaling pathway is deceptively simple, the consequences of Notch activation on cell fate are complex and context-dependent. The manner in which other signaling pathways cross-talk with Notch signaling appears to be extraordinarily complex. Recent observations have demonstrated the importance of endocytosis, multiple ubiquitin ligases, non-visual beta-arrestins and hypoxia in modulating Notch signaling. Structural biology is shedding light on the molecular mechanisms whereby Notch interacts with its nuclear partners. Genomics is slowly unraveling the puzzle of Notch target genes in several systems. At the same time, interest in modulating Notch signaling for medical purposes has dramatically increased. Over the last few years we have learned much about Notch signaling in cancer, immune disorders, neurological disorders and most recently, stroke. The role of Notch signaling in normal and transformed stem cells is under intense investigation. Some Notch-modulating drugs are already in clinical trials, and others at various stages of development. This review will focus on the most recent findings on Notch signaling in cancer and discuss their potential clinical implications.

Antineoplastic Agents↗
PubMed2006

NUMB is a break of WNT-Notch signaling cycle.

Notch, FGF and WNT signaling pathways cross-talk during embryogenesis, tissue regeneration and carcinogenesis. Notch-ligand binding to Notch receptors leads to the cleavage of Notch receptors and the following nuclear translocation of Notch intracellular domain (NICD) to induce transcriptional activation of Notch target genes. Notch signaling inhibitors, NUMB and NUMB-like (NUMBL), are docking proteins with PTB domain. We searched for the TCF/LEF-binding site within the promoter region of NUMB and NUMBL genes. Because two TCF/LEF-binding sites were identified within human NUMB promoter based on bioinformatics and human intelligence (Humint), comparative integromics analyses on NUMB orthologs were further performed. Chimpanzee NUBM gene, consisting of 13 exons, was identified within NW_115880.1 genome sequence. XM_510045.1 was not the correct coding sequence for chimpanzee NUMB. Chimpanzee NUMB gene was found to encode a 651-amino-acid protein showing 99.5, 93.9 and 82.6% total-amino-acid identity with human NUMB, mouse Numb and chicken numb, respectively. Human NUMB mRNA was expressed in placenta, ES cells, neural tissues, trachea, testis, uterus, thymus, coronary artery as well as in a variety of tumors, such as cervical cancer, tong tumor, brain tumor, colorectal and breast cancer. Although distal TCF/LEF-binding site within human NUMB promoter was conserved only among primate NUMB orthologs, proximal TCF/LEF-binding site was conserved among primate and rodent NUMB orthologs. NUMB, JAG1, FGF18, FGF20 and SPRY4 are potent targets of the canonical WNT signaling pathway in progenitor cells. NUMB inhibits Notch signaling in progenitor cells to induce differentiation, while JAG1 activates Notch signaling in stem cells to maintain self-renewal potential. Because Notch signaling inhibitor NUMB was identified as the safe apparatus for the WNT - Notch signaling cycle, epigenetic silencing, deletion and loss-of-function mutation of NUMB gene could lead to carcinogenesis through the dysregulation of the WNT - Notch signaling cycle.

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

Identification of Notch target genes in uncommitted T-cell progenitors: No direct induction of a T-cell specific gene program.

Deregulated Notch signaling occurs in the majority of human T-ALL. During normal lymphoid development, activation of the Notch signaling pathway poses a T-cell fate on hematopoietic progenitors. However, the transcriptional targets of the Notch pathway are largely unknown. We sought to identify Notch target genes by inducing Notch signaling in human hematopoietic progenitors using two different methods: an intracellular signal through transfection of activated Notch and a Notch-receptor dependent signal by interaction with its ligand Delta1. Gene expression profiles were generated and evaluated with respect to expression profiles of immature thymic subpopulations. We confirmed HES1, NOTCH1 and NRARP as Notch target genes, but other reported Notch targets, including the genes for Deltex1, pre-T-cell receptor alpha and E2A, were not found to be differentially expressed. Remarkably, no induction of T-cell receptor gene rearrangements or transcription of known T-cell specific genes was found after activation of the Notch pathway. A number of novel Notch target genes, including the transcription factor TCFL5 and the HOXA cluster, were identified and functionally tested. Apparently, Notch signaling is essential to open the T-cell pathway, but does not initiate the T-cell program itself.

Animals↗
PubMed1998

Prevalence and relevance of a septal diastolic notch during dobutamine stress echocardiography.

BACKGROUND: Dobutamine stress echocardiography has become an accepted simple and inexpensive method of detecting coronary artery disease. In this pharmacological stress test, particular attention has been paid to transient systolic wall motion abnormalities. Our group has noted an abnormal diastolic ventricular septal motion, a 'diastolic notch', during dobutamine stress echocardiography that has not been previously described. METHODS AND RESULTS: To find out whether this anomalous septal motion is related to coronary artery disease we have analysed the stress studies of 125 patients (69 men, age 61 +/- 9 years) with chest pain, no previous myocardial infarction and no left bundle branch block, who underwent a dobutamine stress test. Dobutamine was infused up to 40 mu.kg.l-1 min-1 in 3 min stages. A positive stress test was defined as the appearance of transient asynergy. Dobutamine time was the time from the infusion of dobutamine to the appearance of transient asynergy. The diastolic notch time was the time at which diastolic notch was first detected. Diastolic notch was detected in 21 patients with single coronary artery disease, 19 of whom had a severe left anterior descending artery stenosis. Diastolic notch was present in 19 out of 27 patients (70%) with single left anterior descending stenosis. Twenty-six out of 44 patients with multivessel coronary artery disease had evidence of a diastolic notch and 20 of these 26 had severe stenosis of the left anterior descending artery. Finally, all three patients with left main coronary artery disease had a diastolic notch while no patient with angiographically normal coronary arteries had this sign. In patients with a diastolic notch and a positive dobutamine stress test, diastolic notch time was shorter than dobutamine time (9 +/- 4 min vs 11 +/- 3 min, P < 0.05). CONCLUSIONS: In patients without previous myocardial infarction and without left bundle branch block (1) the appearance of a septal diastolic notch during dobutamine stress echocardiography is very specific for the presence of coronary artery disease; (2) the detection of diastolic notch is mostly related to the existence of severe left anterior descending artery stenosis; (3) diastolic notch precedes the development of ventricular asynergy.

Aged↗
PubMed1989

The notch gene product is a glycoprotein expressed on the cell surface of both epidermal and neuronal precursor cells during Drosophila development.

The Notch locus of Drosophila melanogaster is one of a small number of zygotically acting "neurogenic" genes involved in the correct segregation of neural from epidermal lineages during embryogenesis as well as in other postembryonic developmental events. We have generated antibody probes against three regions of the Notch protein to study the expression of Notch and begin a biochemical characterization of the protein. Consistent with predictions based on DNA sequence data, here we gather evidence showing that Notch encodes a large, glycosylated surface protein with an apparent molecular mass of 300 kD: (a) all three antibodies detect Notch on Western blots as a high molecular mass, primarily full-length product; (b) immunoelectron microscopy localizes the Notch protein to the cell membrane; and (c) lentil lectin column binding demonstrates that the protein is glycosylated, indicative of its surface protein nature. In general, the distribution of the Notch protein coincides with that of the Notch transcript determined previously by in situ hybridizations. Notch is expressed in a much wider range of tissue types than those disrupted in the neurogenic mutant, as determined by antibody localization. Early labeling in the blastoderm appears ubiquitous except for the pole cells, but as development proceeds some distinctive features emerge: stronger staining is seen within the germ band layer where neuroblast delamination occurs, and the developing embryonic nervous system shows pronounced axonal staining. In third instar larvae, Notch is expressed in imaginal disks and in the central nervous system. Based on these results, certain models for how Notch controls the neuroblast cell fate choice are eliminated. We discuss how Notch may function in this choice as well as in other lineage fate determinations.

Animals↗
PubMed2006

Audiogram notches in noise-exposed workers.

OBJECTIVES: Diagnostic criteria for noise-induced hearing loss include the audiometric notch, yet no standardized definition exists. This study tested whether objective notch metrics could match the clinical judgments of an expert panel. DESIGN: A panel of occupational physicians, otolaryngologists, and audiologists reviewed audiograms of noise-exposed workers. In a two-sample process, the panel judged whether a notch was present and whether hearing loss had progressed in a notch pattern. Quantitative notch metrics were compared against expert decisions. RESULTS: At least five of six experts agreed about notch identification in 71 and 72% of the cases in the two samples, and agreement about notch progression was 61 and 67%. Notch depth and professional specialty appeared to affect notch judgments. Despite this variability, a notch metric showed excellent agreement with expert notch consensus in each sample (94.7 and 96.6%; kappa = 0.88 and 0.92). CONCLUSIONS: Audiogram notch metrics can agree with expert clinical consensus and assist in the surveillance of noise-exposed workers.

Adult↗
PubMed1989

Detection and discrimination of spectral peaks and notches at 1 and 8 kHz.

The ability of subjects to detect and discriminate spectral peaks and notches in noise stimuli was determined for center frequencies fc of 1 and 8 kHz. The signals were delivered using an insert earphone designed to produce a flat frequency response at the eardrum for frequencies up to 14 kHz. In experiment I, subjects were required to distinguish a broadband reference noise with a flat spectrum from a noise with either a peak or a notch at fc. The threshold peak height or notch depth was determined as a function of bandwidth of the peak or notch (0.125, 0.25, or 0.5 times fc). Thresholds increased with decreasing bandwidth, particularly for the notches. In experiment II, subjects were required to detect an increase in the height of a spectral peak or a decrease in the depth of a notch as a function of bandwidth. Performance was worse for notches than for peaks, particularly at narrow bandwidths. For both experiments I and II, randomizing (roving) the overall level of the stimuli had little effect at 1 kHz, but tended to impair performance at 8 kHz, particularly for notches. Experiments III-VI measured thresholds for detecting changes in center frequency of sinusoids, bands of noise, and spectral peaks or notches in a broadband background. Thresholds were lowest for the sinusoids and highest for the peaks and notches. The width of the bands, peaks, or notches had only a small effect on thresholds. For the notches at 8 kHz, thresholds for detecting glides in center frequency were lower than thresholds for detecting a difference in center frequency between two steady sounds. Randomizing the overall level of the stimuli made frequency discrimination of the sinusoids worse, but had little or no effect for the noise stimuli. In all six experiments, performance was generally worse at 8 kHz than at 1 kHz. The results are discussed in terms of their implications for the detectability of spectral cues introduced by the pinnae.

Adult↗
PubMed2000

Neoplastic transformation by Notch requires nuclear localization.

Notch proteins are plasma membrane-spanning receptors that mediate important cell fate decisions such as differentiation, proliferation, and apoptosis. The mechanism of Notch signaling remains poorly understood. However, it is clear that the Notch signaling pathway mediates its effects through intercellular contact between neighboring cells. The prevailing model for Notch signaling suggests that ligand, presented on a neighboring cell, triggers proteolytic processing of Notch. Following proteolysis, it is thought that the intracellular portion of Notch (N(ic)) translocates to the nucleus, where it is involved in regulating gene expression. There is considerable debate concerning where in the cell Notch functions and what proteins serve as effectors of the Notch signal. Several Notch genes have clearly been shown to be proto-oncogenes in mammalian cells. Activation of Notch proto-oncogenes has been associated with tumorigenesis in several human and other mammalian cancers. Transforming alleles of Notch direct the expression of truncated proteins that primarily consist of N(ic) and are not tethered to the plasma membrane. However, the mechanism by which Notch oncoproteins (generically termed here as N(ic)) induce neoplastic transformation is not known. Previously we demonstrated that N1(ic) and N2(ic) could transform E1A immortalized baby rat kidney cells (RKE) in vitro. We now report direct evidence that N1(ic) must accumulate in the nucleus to induce transformation of RKE cells. In addition, we define the minimal domain of N1(ic) required to induce transformation and present evidence that transformation of RKE cells by N1(ic) is likely to be through a CBF1-independent pathway.

Animals↗
PubMedDate not supplied

Differences in femoral notch anatomy between men and women: a magnetic resonance imaging study.

BACKGROUND: Research has shown that variations in femoral intercondylar notch morphometry may be a predisposing factor for noncontact anterior cruciate ligament injury. HYPOTHESIS: There are anatomic differences in the anterior cruciate ligament and femoral notch between men and women. STUDY DESIGN: Descriptive anatomic study. METHODS: Using magnetic resonance imaging, we performed a three-dimensional analysis of the femoral intercondylar notch morphometry to look for differences in femoral notch and anterior cruciate ligament volumes between men and women. Axial plane magnetic resonance imaging scans were performed on 96 knees in 48 asymptomatic subjects. Digital measurements were taken of femoral notch area, anterior cruciate ligament area, notch width, and bicondylar width, within defined parameters of the femoral notch. The notch and anterior cruciate ligament volumes were then calculated. Analysis of variance was performed using sex, height, and weight as covariates. RESULTS: The volume of the femoral notch was found to be statistically smaller in women compared with men; this difference was primarily related to height. A similar relationship was found for anterior cruciate ligament volume. A statistically significant correlation was found between femoral notch volume and anterior cruciate ligament volume; patients with smaller notches also had smaller anterior cruciate ligaments. CONCLUSIONS: Our results suggest that there is a difference in femoral notch and anterior cruciate ligament volume between men and women, which, in turn, is related to differences in height and weight.

Adult↗
PubMed1999

Notch signaling imposes two distinct blocks in the differentiation of C2C12 myoblasts.

Notch signal transduction regulates expression of downstream genes through the activation of the DNA-binding protein Su(H)/CBF1. In Drosophila most of Notch signaling requires Su(H); however, some Notch-dependent processes occur in the absence of Su(H) suggesting that Notch signaling does not always involve activation of this factor. Using constitutively active forms of Notch lacking CBF1-interacting sequences we identified a Notch signaling pathway that inhibits myogenic differentiation of C2C12 myoblasts in the absence of CBF1 activation. Here we show that ligand-induced Notch signaling suppresses myogenesis in C2C12 myoblasts that express a dominant negative form of CBF1, providing additional evidence for CBF1-independent Notch signal transduction. Surprisingly mutant forms of Notch deficient in CBF1 activation are unable to antagonize MyoD activity, despite the fact that they inhibit myogenesis. Moreover, Notch-induced antagonism of MyoD requires CBF1 suggesting that the CBF1-dependent pathway mediates a cell-type-specific block in the myogenic program. However, Notch signaling in the absence of CBF1 activation blocks both myogenesis and osteogenesis, indicative of a general block in cellular differentiation. Taken together our data provide evidence for two distinct Notch signaling pathways that function to block differentiation at separate steps during the process of myogenesis in C2C12 myoblasts.

3T3 Cells↗
PubMed2006

Notch-1 up-regulation and signaling following macrophage activation modulates gene expression patterns known to affect antigen-presenting capacity and cytotoxic activity.

Notch signaling has been extensively implicated in cell-fate determination along the development of the immune system. However, a role for Notch signaling in fully differentiated immune cells has not been clearly defined. We have analyzed the expression of Notch protein family members during macrophage activation. Resting macrophages express Notch-1, -2, and -4, as well as the Notch ligands Jagged-1 and -2. After treatment with LPS and/or IFN-gamma, we observed a p38 MAPK-dependent increase in Notch-1 and Jagged-1 mRNA and protein levels. To study the role of Notch signaling in macrophage activation, we forced the transient expression of truncated, active intracellular Notch-1 (Notch-IC) proteins in Raw 264.7 cells and analyzed their effects on the activity of transcription factors involved in macrophage activation. Notch-IC increased STAT-1-dependent transcription. Furthermore, Raw 264.7 Notch-IC stable transfectants increased STAT1-dependent transcription in response to IFN-gamma, leading to higher expression of IFN regulatory factor-1, suppressor of cytokine signaling-1, ICAM-1, and MHC class II proteins. This effect was independent from an increase of STAT1 Tyr or Ser phosphorylation. However, inducible NO synthase expression and NO production decreased under the same conditions. Our results show that Notch up-regulation and subsequent signaling following macrophage activation modulate gene expression patterns known to affect the function of mature macrophages.

Active Transport, Cell Nucleus↗
PubMed2005

Increased protein expression of the PTEN tumor suppressor in the presence of constitutively active Notch-1.

Mammalian Notch-1 is part of an evolutionarily conserved family of transmembrane receptors best known for involvement in cell fate decisions. Mutations that result in Notch-1 activation result in T-lineage oncogenesis. In other cell lineages, however, studies have indicated that cooperation with cellular signaling pathways, such as Ras, is necessary for Notch-mediated oncogenesis and in some settings, Notch-1 has been reported to function as a tumor suppressor. In order to test the hypothesis that the Notch-1 pathway exhibits cross-talk with Ras/Raf/MEK/ERK, the constitutively active cytoplasmic portion of Notch-1 was introduced into 293 HEK fibroblasts via retroviral transduction. ERK-1,-2 activation was markedly increased in cells expressing constitutively active Notch-1. These cells exhibited a more rounded morphology as compared to 293 cells transduced with an empty vector or parental 293 cells. These observations correlated with decreased total and phosphorylated focal adhesion kinase protein (FAK). Subsequent examination of phosphatase and tensin homolog deleted on chromosome 10 (PTEN) revealed that total and phosphorylated PTEN protein was elevated in cells expressing constitutively active Notch-1. Loss of Akt phosphorylation was also observed in cells bearing activated Notch-1. Two potential binding sites for the Notch effector CBF-1 were identified in the human PTEN promoter sequence. A PTEN promoter luciferase reporter exhibited increased activity in the presence of Notch-1 signaling. These data indicate that Notch-1 can participate in cross-talk with other signaling pathways such as Ras/Raf/MEK/ERK through the regulation of the PTEN tumor suppressor.

Actins↗
PubMed2002

Notch activation during endothelial cell network formation in vitro targets the basic HLH transcription factor HESR-1 and downregulates VEGFR-2/KDR expression.

Angiogenesis is essential for normal homeostasis, wound healing, and tumor growth and involves a switch in endothelial cell (EC) phenotype from quiescence to migration, proliferation and network formation, and back to quiescence. The notch signaling pathway is critically involved in cell fate decisions during development, and mice deficient in several notch/notch ligand genes have vascular phenotypes. Here we show that notch signaling is activated during EC capillary-like network formation in vitro and that EC express transcripts for notch 1, notch 4, the notch ligand delta 4, and the putative notch processing enzymes ADAM-10 and presenilin. Expression of dominant negative notch blocks network formation; however, constitutively active notch (NICD) does not induce morphologic changes. Furthermore, both EC network formation and expression of activated notch 1 or notch 4 induce expression of the bHLH transcription factor HESR-1 and downregulate the known HESR-1 target VEGFR-2 (KDR). Notch-mediated reduction in VEGFR-2 expression results in decreased EC proliferation in response to VEGF but not bFGF. These data suggest that HESR-1 may be involved in the phenotypic changes that characterize the progression from EC proliferation and migration to network formation and quiescence.

Basic Helix-Loop-Helix Proteins↗
PubMed2004

Regulation of notch endosomal sorting and signaling by Drosophila Nedd4 family proteins.

The Notch receptor mediates a short-range signal that regulates many cell fate decisions. The misregulation of Notch has been linked to cancer and to developmental disorders. Upon binding to its ligands, Delta (Dl) or Serrate (Ser), the Notch ectodomain is shed by the action of an ADAM protease. The Notch intracellular domain is subsequently released proteolytically from the membrane by Presenilin and translocates to the nucleus to activate the transcription factor, Suppressor of Hairless. We show in Drosophila that Notch signaling is limited by the activity of two Nedd4 family HECT domain proteins, Suppressor of deltex [Su(dx)] and DNedd4. We rule out models by which Su(dx) downregulates Notch through modulating Deltex or by limiting the adherens junction accumulation of Notch. Instead, we show that Su(dx) regulates the postendocytic sorting of Notch within the early endosome to an Hrs- and ubiquitin-enriched subdomain en route to the late endosome. We propose a model in which endocytic sorting of Notch mediates a decision between its activation and downregulation. Such intersections between trafficking routes may provide key points at which other signals can modulate Notch activity in both normal development and in the pathological misactivation of Notch.

Animals↗
PubMed2005

Notch signaling: distinct ligands induce specific signals during lymphocyte development and maturation.

Notch signaling is a highly conserved pathway involved in cell fate choice during development with Delta and Jagged constituting the two evolutionary conserved families of Notch ligands. These ligands are transmembrane proteins with conserved biochemical structure that share their receptors and signal through a common mechanism. Upon ligand binding Notch receptors are proteoliticaly cleaved, the intracellular domain of Notch (NICD) is released and translocated to the nucleus, where it activates target genes. In mammals, four receptors and five ligands have been described. Delta-1, Delta-3 and Delta-4 are homologues to Drosophila Delta and Jagged-1 and Jagged-2 to Drosophila Serrate. Despite strong domain homology, there is growing evidence that signals transmitted through Delta or Jagged ligands can differentially affect the target cell. At least during embryonic development, Notch receptors and Notch ligands functions cannot be compensated by other members. Knock-out mice for Notch-1, Notch-2, Delta-1 and Jagged-1 are embryonic lethal . Similarly, mice heterozygous for Delta-4 inactivation also die before birth . Invalidation of Jagged-2 results in defaults in thymus morphology and gammadelta development . Altogether, these data suggest that each Notch member can exert unique specific effects. In this review, we will thus focus on recent data about differential effects of Notch ligands on T cell development and differentiation. In light of recent biochemical and molecular advances on Notch-signaling pathway, we will examine how specific effects can be mediated by a given ligand.

Animals↗
PubMedDate not supplied

Expression and distribution of notch protein members in human placenta throughout pregnancy.

Notch signaling is an evolutionarily conserved mechanism used by invertebrates and vertebrates to control cell fates through close-range cell interactions. Four Notch receptors have been identified in vertebrates and different ligands, divided into Delta-like and Serrate-like (Jagged). Several studies have demonstrated that Notch signaling is involved in different branches of the cell fate decision tree: differentiation, proliferation and apoptosis. These three processes are finely regulated in human placenta in order to allow a successful pregnancy and a correct fetal growth. Moreover, Notch and its ligands participate in the vascular remodelling and stabilization, other two processes much important and ticklish in human placenta. So, we decided to investigate the pattern of expression of Notch-1, Notch-4 and Jagged-1, together with two members related to Notch pathway and involved in angiogenesis: VEGF and p21, in human placenta during gestation by immunoblotting and immunohistochemistry. We showed a modulation of Notch proteins throughout the pregnancy; in particular we showed a slight decrease of Notch-1 throughout pregnancy, with a decreased cytoplasmic staining from the first to the third trimester of gestation in cytotrophoblast and syncytiotrophoblast. In contrast Jagged-1 showed an increase throughout pregnancy especially in syncytiotrophoblast and stroma during the third trimester of gestation. In addition, we found by immunoblotting an increase of VEGF expression from the first to the third trimester and an intense VEGF expression inside endothelial cells throughout the gestation as also confirmed by immunohistochemistry. We also showed a decrease of p21 expression during the pregnancy both through immunoblotting and immunohistochemistry assays. Moreover, we observed Notch localization in extravillous trophoblast cells that are able to invade the decidualized endometrium. Our results suggest an involvement of Notch signaling in regulation of placental cell fate decision and in angiogenesis that are dramatically important to maintain a normal physiology of this organ during pregnancy.

Calcium-Binding Proteins↗
PubMed2006

Spatially localized Kuzbanian required for specific activation of Notch during border cell migration.

The transmembrane receptor Notch is used repeatedly during development for a variety of essential functions. During Drosophila oogenesis, Notch activity is required first to specify particular follicle cell fates, then to promote the differentiation of all follicle cell types, to promote border cell migration, and then to form dorsal appendages, raising the question as to how Notch activity is spatially and temporally regulated. Here we show the Notch activity pattern during oogenesis. Notch activation was found in many follicle cells at stage 6 but then at stage 9 was restricted to migrating border cells, despite uniform expression of Delta. Expression of Kuzbanian (KUZ), a metalloproteinase that can activate Notch as well as cleave other substrates, is enriched in border cells at stage 9; and dominant-negative KUZ caused a strong border cell migration defect, without affecting expression of markers of border cell fate or follicle cell differentiation. Constitutively active Notch rescued the migration defect due to dominant-negative KUZ, and conditional alleles of Delta and Notch also exhibited border cell migration defects. Expression of two different reporters of Notch activity was lost upon expression of dominant-negative KUZ. Taken together these results show that Notch activation and KUZ expression are restricted to border cells at stage 9 of oogenesis and are required for migration, but not differentiation, of these cells. This represents a previously unrecognized mechanism for achieving spatial restriction of Notch signaling.

Amino Acid Motifs↗