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PubMed1996

Autonomous and nonautonomous Notch functions for embryonic muscle and epidermis development in Drosophila.

The Notch (N) gene encodes a cell signaling protein that mediates neuronal and epidermal determination in Drosophila embryos. N also regulates several aspects of myogenic development; embryos lacking N function have too many muscle founder cells and fail to properly differentiate somatic muscle. To identify cell-autonomous requirements for Notch function during muscle development, we expressed a Notch minigene in the mesoderm, but not in the ectoderm, of amorphic N-embryos. In these embryos, muscle founder hypertrophy is rescued, indicating that Notch is autonomously required by mesoderm cells to regulate the proper number of muscle founders. However, somatic muscle differentiation is only partially normalized, suggesting that Notch is also required in the ectoderm for proper muscle development. Additionally, mesodermal expression of Notch partially rescues epidermal development in overlying neurogenic ectoderm. This is unexpected, since previous studies suggest that Notch is autonomously required by proneural ectoderm cells for epidermal development. Mesodermal expression of a truncated Notch protein lacking the extracellular domain does not rescue ventral epidermis, suggesting that the extra-cellular domain of Notch can non-autonomously rescue epidermal development across germ layers.

Animals↗
PubMed1997

Notch signalling regulates veinlet expression and establishes boundaries between veins and interveins in the Drosophila wing.

The veins in the Drosophila wing have a characteristic width, which is regulated by the activity of the Notch pathway. The expression of the Notch-ligand Delta is restricted to the developing veins, and coincides with places where Notch transcription is lower. We find that this asymmetrical distribution of ligand and receptor leads to activation of Notch on both sides of each vein within a territory of Delta-expressing cells, and to the establishment of boundary cells that separate the vein from adjacent interveins. In these cells, the expression of the Enhancer of split gene m beta is activated and the transcription of the vein-promoting gene veinlet is repressed, thus restricting vein differentiation. We propose that the establishment of vein thickness utilises a combination of mechanisms that include: (1) independent regulation of Notch and Delta expression in intervein and vein territories, (2) Notch activation by Delta in cells where Notch and Delta expression overlaps, (3) positive feedback on Notch transcription in cells where Notch has been activated and (4) repression of veinlet transcription by E(spl)m beta and maintenance of Delta expression by veinlet/torpedo activity.

Animals↗
PubMed1998

Interactions among Delta, Serrate and Fringe modulate Notch activity during Drosophila wing development.

The Notch signalling pathway plays an important role during the development of the wing primordium, especially of the wing blade and margin. In these processes, the activity of Notch is controlled by the activity of the dorsal specific nuclear protein Apterous, which regulates the expression of the Notch ligand, Serrate, and the Fringe signalling molecule. The other Notch ligand, Delta, also plays a role in the development and patterning of the wing. It has been proposed that Fringe modulates the ability of Serrate and Delta to signal through Notch and thereby restricts Notch signalling to the dorsoventral boundary of the developing wing blade. Here we report the results of experiments aimed at establishing the relationships between Fringe, Serrate and Delta during wing development. We find that Serrate is not required for the initiation of wing development but rather for the expansion and early patterning of the wing primordium. We provide evidence that, at the onset of wing development, Delta is under the control of apterous and might be the Notch ligand in this process. In addition, we find that Fringe function requires Su(H). Our results suggest that Notch signalling during wing development relies on careful balances between positive and dominant negative interactions between Notch ligands, some of which are mediated by Fringe.

Animals↗
PubMed2000

Relationships between extramacrochaetae and Notch signalling in Drosophila wing development.

The function of extramacrochaetae is required during the development of the Drosophila wing in processes such as cell proliferation and vein differentiation. extramacrochaetae encodes a transcription factor of the HLH family, but unlike other members of this family, Extramacrochaetae lacks the basic region that is involved in interaction with DNA. Some phenotypes caused by extramacrochaetae in the wing are similar to those observed when Notch signalling is compromised. Furthermore, maximal levels of extramacrochaetae expression in the wing disc are restricted to places where Notch activity is higher, suggesting that extramacrochaetae could mediate some aspects of Notch signalling during wing development. We have studied the relationships between extramacrochaetae and Notch in wing development, with emphasis on the processes of vein formation and cell proliferation. We observe strong genetic interaction between extramacrochaetae and different components of the Notch signalling pathway, suggesting a functional relationship between them. We show that the higher level of extramacrochaetae expression coincides with the domain of expression of Notch and its downstream gene Enhancer of split-m(beta). The expression of extramacrochaetae at the dorso/ventral boundary and in boundary cells between veins and interveins depends on Notch activity. We propose that at least during vein differentiation and wing margin formation, extramacrochaetae is regulated by Notch and collaborates with other Notch-downstream genes such as Enhancer of split-m(beta).

Animals↗
PubMed2000

Ligand endocytosis drives receptor dissociation and activation in the Notch pathway.

Endocytosis of the ligand delta; is required for activation of the receptor Notch during Drosophila development. The Notch extracellular domain (NotchECD) dissociates from the Notch intracellular domain (NotchICD) and is trans-endocytosed into delta;-expressing cells in wild-type imaginal discs. Reduction of dynamin-mediated endocytosis in developing eye and wing imaginal discs reduces Notch dissociation and Notch signalling. Furthermore, dynamin-mediated delta endocytosis is required for Notch trans-endocytosis in Drosophila cultured cell lines. Endocytosis-defective delta proteins fail to mediate trans-endocytosis of Notch in cultured cells, and exhibit aberrant subcellular trafficking and reduced signalling capacity in Drosophila. We suggest that endocytosis into delta-expressing cells of NotchECD bound to delta plays a critical role during activation of the Notch receptor and is required to achieve processing and dissociation of the Notch protein.

Animals↗
PubMed2002

Involvement of a proline-rich motif and RING-H2 finger of Deltex in the regulation of Notch signaling.

The Notch pathway is an evolutionarily conserved signaling mechanism that is essential for cell-cell interactions. The Drosophila deltex gene regulates Notch signaling in a positive manner, and its gene product physically interacts with the intracellular domain of Notch through its N-terminal domain. Deltex has two other domains that are presumably involved in protein-protein interactions: a proline-rich motif that binds to SH3-domains, and a RING-H2 finger motif. Using an overexpression assay, we have analyzed the functional involvement of these Deltex domains in Notch signaling. The N-terminal domain of Deltex that binds to the CDC10/Ankyrin repeats of the Notch intracellular domain was indispensable for the function of Deltex. A mutant form of Deltex that lacked the proline-rich motif behaved as a dominant-negative form. This dominant-negative Deltex inhibited Notch signaling upstream of an activated, nuclear form of Notch and downstream of full-length Notch, suggesting the dominant-negative Deltex might prevent the activation of the Notch receptor. We found that Deltex formed a homo-multimer, and mutations in the RING-H2 finger domain abolished this oligomerization. The same mutations in the RING-H2 finger motif of Deltex disrupted the function of Deltex in vivo. However, when the same mutant was fused to a heterologous dimerization domain (Glutathione-S-Transferase), the chimeric protein had normal Deltex activity. Therefore, oligomerization mediated by the RING-H2 finger motif is an integral step in the signaling function of Deltex.

Amino Acid Motifs↗
PubMed2006

Notch signaling enhances nestin expression in gliomas.

Recent findings suggest that Notch signaling is active in brain tumors and stem cells, and that stem cells or cells with progenitor characteristics contribute to brain tumor formation. These stem cells are marked by expression of several markers, including nestin, an intermediate filament protein. We have studied how the Notch signaling pathway affects nestin expression in brain tumors. We find that Notch receptors and ligands are expressed in vitro and in human samples of glioblastomas, the highest grade of malignant gliomas. In culture, Notch activity activates the nestin promoter. Activation of the Notch pathway also occurs in a glioblastoma multiforme mouse model induced by Kras, with translational regulation playing a role in Notch expression. Combined activation of Notch and Kras in wild-type nestin-expressing cells leads to their expansion within the subventricular zone and retention of proliferation and nestin expression. However, activation of Notch alone is unable to induce this cellular expansion. These data suggest that Notch may have a contributing role in the stem-like character of glioma cells.

Animals↗
PubMed2006

[Role of Cre-loxP-mediated conditional gene targeting in understanding the function of Notch receptors].

The Notch family of cell surface receptors and their ligands constitute an evolutionarily conserved signaling pathway that is used by invertebrates and vertebrates to regulate a broad spectrum of cell specification events through local cell interactions. After ligand binding Notch receptor undergoes proteolytic processing ultimately liberating the cytoplasmic domain of the Notch receptor which translocates to the nucleus and activates target genes. In all animal models tested, mutations in Notch genes invariably resulted in developmental abnormalities. In mammals, Notch signaling controls key stages of lymphocyte differentiation as well as activation and several abnormalities in Notch pathway have been suggested to cause human leukemias. Cre-loxP mediated conditional gene targeting significantly contributed to our current understanding of the physiological roles of different Notch family members in hematopoietic compartment. This technique helped to overcome embryonic lethality of Notch mutants providing the opportunity to inactivate specific Notch gene in adulthood.

Animals↗
PubMed1995

Notch-related genes in animal development.

The Drosophila melanogaster gene Notch is central to many cell differentiation events during development. It encodes a large transmembrane signal receptor protein that acts in a poorly understood mechanism of communication affecting the choice of alternative differentiation fates by cells in close proximity. Genes with homology to Notch have been isolated from the nematode Caenorhabditis elegans and a number laboratories, including our own, have isolated multiple vertebrate Notch homologs. In this article we briefly outline the current state of research on Notch and our contribution to it. First, we examine the structure of Notch-related proteins. We then examine the requirements for Notch activity in the development of different organisms and how genetic and transgenic studies are helping us to understand the mechanism(s) by which these proteins function. We present models for the action of Notch receptors during signal transduction and for the interaction of multiple vertebrate Notch receptors. Finally, we discuss current ideas about the role played by Notch in differentiation and cell-cell communication.

Amino Acid Sequence↗
PubMed1997

The expression and function of Notch pathway genes in the developing rat eye.

The Notch gene plays a role in the development of disparate tissues in multiple organisms. Because the vertebrate eye is an excellent model system for both patterning and cell fate determination, two processes that can involve Notch, we examined the expression patterns of Notch 1 and Notch 2, and their ligands Delta and Jagged, in the developing rat eye. Notch 1 and Delta were found to be expressed in the neural retina during the period of cell fate determination and differentiation. Notch 2 was found to be expressed in the non-neuronal derivatives of the optic cup, including the pigment epithelium, optic stalk, and ciliary body. Jagged was expressed in distinct regions within the optic vesicle, ciliary body, and lens, with patterns that changed over time. The potential function of Notch 1 in cell-type specification and differentiation was examined by introducing a constitutively active form of Notch 1 in vivo using a replication-incompetent retrovirus. This form of Notch 1 was found to cause abnormal growth and interfere with the differentiation of multiple retinal cell types.

Aging↗
PubMed2007

Proposal for classification of the suprascapular notch: a study on 423 dried scapulas.

The present study proposes a simple and reproducible method to classify the morphology of the suprascapular notch (SSN), on the basis of specific geometrical parameters that clearly distinguish one type from another. Four hundred twenty-three dried scapulas from the Department of Anatomy in the University of Cologne, Germany, were examined. Five types of SSN were observed: type I, without a discrete notch, 35 (8.3%); type II, a notch that was longest in its transverse diameter, 177 (41.85%); type III, a notch that was longest in its vertical diameter, 177 (41.85%); type IV, a bony foramen, 31 (7.3%); type V, a notch and a bony foramen, 3 (0.7%). For the vertical diameter, we took the maximal diameter of the notch perpendicular to the imaginary line that joins the two superior corners of the notch. For the transverse diameter, we took the diameter perpendicular to the midpoint of the vertical diameter. This classification based on the vertical and the transverse diameters of the SSN suggested a clear distinction of the notch types. This simple classification included all the anatomical variations of the SSN. Using this method, the clinician will be able to define easily and quickly the notch type on a plain radiograph, and perhaps be able to correlate suprascapular nerve entrapment with a specific type of SSN.

Anthropometry↗
PubMed2006

Notch-1 down-regulation by curcumin is associated with the inhibition of cell growth and the induction of apoptosis in pancreatic cancer cells.

BACKGROUND: Notch signaling plays a critical role in maintaining the balance between cell proliferation, differentiation, and apoptosis, and thereby may contribute to the development of pancreatic cancer. Therefore, the down-regulation of Notch signaling may be a novel approach for pancreatic cancer therapy. It has been reported that curcumin down-regulates many genes that are known to promote survival and also up-regulates genes that are known promoters of apoptosis in pancreatic cancer cells in vitro. It also has been reported that there is cross-talk between Notch-1 and another major cell growth and apoptotic regulatory pathway, the nuclear factor kappaB (NF-kappaB) pathway, which is down-regulated by both curcumin and reduction of Notch-1 levels. However, to the authors' knowledge to date, no studies have determined whether the down-regulation of Notch-1 signaling, resulting in the inactivation of NF-kappaB activity, contributes to curcumin-induced cell growth inhibition and apoptosis in pancreatic cancer cells. METHODS: The authors used multiple molecular approaches, such as the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, an apoptosis assay, gene transfection, real-time reverse transcriptase-polymerase chain reaction analysis, Western blot analysis, and an electrophoretic mobility shift assay to measure the DNA binding activity of NF-kappaB. RESULTS: Curcumin inhibited cell growth and induced apoptosis in pancreatic cancer cells. Notch-1, Hes-1, and Bcl-XL expression levels concomitantly were down-regulated by curcumin treatment. These results correlated with the inactivation of NF-kappaB activity and increased apoptosis induced by curcumin. The down-regulation of Notch-1 by small-interfering RNA prior to curcumin treatment resulted in enhanced cell growth inhibition and apoptosis. CONCLUSIONS: The current results provide the first demonstration to the authors' knowledge that the Notch-1 signaling pathway is associated mechanistically with NF-kappaB activity during curcumin-induced cell growth inhibition and apoptosis of pancreatic cells. These results suggest that the down-regulation of Notch signaling by curcumin may be a novel strategy for the treatment of patients with pancreatic cancer.

Antineoplastic Agents↗
PubMed2005

A novel hes5/hes6 circuitry of negative regulation controls Notch activity during neurogenesis.

HES transcriptional repressors are important components of the Notch pathway that regulates neurogenesis from Drosophila to vertebrates. These proteins are normally induced by Notch activity and inhibit neural commitment by antagonizing the activity of proneural genes. We describe here four chick hes genes that are expressed during neurogenesis: three hes5-like genes (hes5-1, hes5-2 and hes5-3) and one hes6-like (hes6-2). We show that hes6-2 represses transcription of the hes5 genes, thus functioning as a negative regulator of Notch signaling. Conversely, hes6-2 may be repressed by hes5 activity. In cells committing to differentiation, we find that hes6-2 is up-regulated by proneural genes and contributes to the proneural program of neuronal commitment by preventing Notch activity in these cells. In neural progenitors, Notch signaling produces an initial burst of hes5 activity, which represses hes6-2. However, as hes5 transcription declines due to negative auto-regulation, hes6-2 may become active and inhibit the remaining hes5 activity to end Notch signaling. These cells can then enter a new cycle of fate decisions and will be kept as progenitors if a new pulse of Notch activity occurs. Maintenance of progenitors during vertebrate neurogenesis therefore requires that these cells go through successive cycles of Notch activity. We propose that the hes5/hes6 circuitry of negative cross-regulations is a conserved feature of the Notch pathway that underlies these cycles in neural progenitors.

Amino Acid Sequence↗
PubMed1998

Assessment of uterine arterial notching as a screening test for adverse pregnancy outcome.

OBJECTIVE: The objective of the study was to evaluate the screening potential of routine uterine arterial Doppler ultrasonography as a predictor of adverse pregnancy outcome. STUDY DESIGN: All women (n = 6579) with singleton pregnancies undergoing a fetal anomaly scan at 18 to 20 weeks' gestation between January 1, 1994, and December 31, 1995, at Ninewells Hospital and Medical School were screened for the presence of uterine arterial notching. Women who had evidence of bilateral notching were rescanned at 22 to 24 weeks' gestation. Outcome measures included proteinuric hypertension, premature separation of the placenta, and birth weight z score. RESULTS: The sensitivity and positive predictive value of uterine arterial notching as a predictor of adverse pregnancy outcomes was low. For all types of notching and disease, outcome sensitivity was never higher than 44% and positive predictive value was never higher than 27%. In contrast, the relative risk of adverse pregnancy outcome in the presence of uterine arterial notching was uniformly high for all disease outcomes (range of relative risk 3.5-30.7). Significant obstetric morbidity was seen in 57% of women with bilateral notches at 18 to 20 weeks' gestation and 72% of women with persistent bilateral notches. CONCLUSIONS: As a screening test for adverse pregnancy outcomes, detection of uterine arterial notching is poor. Nevertheless, the presence of bilateral uterine arterial notching is associated with a significantly increased risk of adverse pregnancy outcome. In units performing routine anomaly screening, the addition of maternal uterine arterial Doppler ultrasonography may help to discriminate this small group of women at high risk.

Adolescent↗
PubMed2001

Expression of presenilin-1 and Notch-1 receptor in human embryonic CNS.

In vitro studies have shown that the Alzheimer's disease-related presenilin-1 protein can mediate Notch-1 receptor cleavage during signalling. In the present study, we compared the distribution of presenilin-1 and Notch-1 receptor immunoreactivities in human embryonic CNS tissue during the first trimester of development. Our aim was to gain insight into whether these proteins are likely to interact functionally during human fetal brain development. CNS material was obtained from routine abortions, cryosectioned and studied by means of immunohistochemistry with antibodies to presenilin-1 and Notch-1. At very early stages of embryonic development (four to five gestational weeks) intensive presenilin-1 immunoreactivity could be seen predominantly in neurites in the ventral horn of the spinal cord, where it overlapped with 200-kDa neurofilament immunoreactivity. Presenilin-1 immunoreactivity was also seen in neuroblasts of the ventricular zone of the tel- and mesencephalon, as well as of the brainstem. Notch-1 receptor appeared in neuronal and ependymal cells throughout the CNS. Seven- to eight-week CNS tissue showed similar patterns of presenilin-1 and Notch-1 receptor expression in the spinal cord and cerebral cortex as was seen at five weeks. Both proteins were localised in the neuroepithelial cell layer lining the ventricles, as well as in the cortical plate layer, where immunoreactivity was seen in the cell bodies. In addition, presenilin-1 immunoreactivity was seen in thin neurites in the subplate of the developing cortex. At 10 weeks, presenilin-1 immunoreactivity was reduced in the spinal cord. These results show that, although presenilin-1 and Notch-1 receptor are localised to the same differentiating cell populations in the human cerebral cortex, making a direct interaction possible, these proteins are otherwise confined to different neurons or neuronal compartments, suggesting a role for presenilin-1 during early CNS differentiation that does not involve Notch-1 receptor processing. Double staining for presenilin-1 in the endoplasmic reticulum and presenilin-1 in the Golgi showed overlap to some extent in investigated CNS regions, but not in neurites. This suggests that presenilin-1 function during neurogenesis is not exclusively correlated to protein processing within the endoplasmic reticulum and Golgi, but that presenilin-1 may also be involved in other processes, such as axonal and dendritic outgrowth or synaptic formation. In summary, our findings provide supportive evidence that the presenilin-1 protein is involved in the development and maturation of the human fetal CNS. The presence of presenilin-1 immunoreactivity in both the cell bodies and neurites of developing neurons strongly suggests divergent mechanisms of function for presenilin-1 during human brain development. These may include interactions with any of the Notch receptor proteins, as well as Notch-independent mechanisms.

Biomarkers↗
PubMed2000

Longitudinal threshold changes in older men with audiometric notches.

Age-related hearing loss (presbycusis) is a multifactorial process that results chiefly from the accumulating effects of noise damage and aging on the cochlea. Noise damage is typically evidenced clinically by a discrete elevation (notch) of the auditory thresholds in the 3-6 kHz region of the audiogram whereas aging affects the highest frequencies first. To determine whether the presence of such high-frequency notches influences auditory aging, we examined the 15 year change in audiometric thresholds in 203 men from the Framingham Heart Study cohort. The mean age at the first hearing test was 64 years (range 58-80). Occupational and recreational noise exposure over the 15 years was assumed to be minimal due to the age of the subjects. The presence or absence of a notch was determined using a piecewise linear/parabolic curve fitting strategy. A discrete elevation of the pure-tone thresholds of 15-34 dB in the 3-6 kHz region was deemed a small notch (N1), and elevations of 35 dB or greater were deemed large notches (N2). Absence of a notch (N0) was encoded those ears with <15 dB elevation in the 3-6 kHz region. The presence and absence of notches correlated with the subjects' history of noise exposure. The 15 year pattern of change in age-adjusted pure-tone thresholds varied significantly by notch category. There was less change over time in the notch frequencies (3-6 kHz) and significantly greater change in the adjacent frequency of 2 kHz in the N2 group as compared to the N0 and N1 groups. The adjacent frequency of 8 kHz showed a significant, but smaller, change in the N1 group as compared to the N0 and N2 groups. The change at 2 kHz was independent of the starting hearing level at E15, whereas the changes at 4-8 kHz were influenced by the hearing level at E15. These data suggest that the noise-damaged ear does not 'age' at the same rate as the non-noise damaged ear. The finding of increased loss at 2 kHz suggests that the effects of noise damage may continue long after the noise exposure has stopped. The mechanism for this finding is unknown but presumably results from prior noise-induced damage to the cochlea.

Aged↗
PubMedDate not supplied

Performance of a real-time dicrotic notch detection and prediction algorithm in arrhythmic human aortic pressure signals.

A novel algorithm for real-time detection and prediction of the dicrotic notch from aortic pressure waves was evaluated in arrhythmic aortic pressure signals from heart failure patients. A simplified model of the arterial tree was used to calculate real-time aortic flow from aortic pressure. The dicrotic notch was detected at the first negative dip from the calculated flow, prediction of the notch was performed using a percentage of the decreasing flow. The performance of the real-time dicrotic notch detection algorithm (RTDND) was evaluated during severe arrhythmia from aortic pressure signals of 12 patients. The RTDND was able to detect the dicrotic notch in 98.1%. No false positive dicrotic notch identifications were observed. Prediction of the dicrotic notch was tested at 40%, 20%, and 0% of the decreasing calculated aortic flow. The mean time-delays to the notch were 68 +/- 14 ms, 55 +/- 12 ms, and 43 +/- 8 ms, respectively. Given these small variability, intra-beat prediction of the dicrotic notch may be used for real-time intra-aortic balloon counterpulsation inflation timing.

Aged↗
PubMed2000

Clinical significance of early diastolic notch depth: uterine artery Doppler velocimetry in the third trimester.

OBJECTIVE: Our purpose was to evaluate the usefulness of early diastolic notch depth in predicting adverse perinatal outcome. STUDY DESIGN: Uterine artery Doppler velocimetry is widely applied in predicting pregnancy outcomes. Recent studies of uterine artery early diastolic notch have demonstrated its usefulness as a marker for fetal well-being. The early diastolic notch represents the reflected blood flow of uteroplacental circulation. This study was carried out under the hypothesis that when early diastolic notch is present evaluating its depth plays a significant role in predicting poor pregnancy outcomes. Its ability to predict adverse perinatal outcomes was evaluated in 198 pregnant women with early diastolic notch after 28 weeks' gestation. RESULTS: The incidence of adverse perinatal outcome (5-minute Apgar score <7, cesarean delivery because of fetal distress, admission to neonatal intensive care unit, fetal growth restriction, or perinatal death) was 90.5% when the notch index was </=0.70. When the notch index range was 0.70 to 0.79, 0.80 to 0.89, and >/=0.90, the respective incidences were 72.3%, 46. 9%, and 28.1%. CONCLUSION: This study suggests that evaluating notch depth in the presence of early diastolic notch on uterine artery velocimetry during the third trimester would be a useful method for predicting adverse perinatal outcomes.

Apgar Score↗