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At least 667 records · Page 37Linked to original sources
PubMed2005

Analysis of Notch function in presomitic mesoderm suggests a gamma-secretase-independent role for presenilins in somite differentiation.

The role of Notch signaling in general and presenilin in particular was analyzed during mouse somitogenesis. We visualize cyclical production of activated Notch (NICD) and establish that somitogenesis requires less NICD than any other tissue in early mouse embryos. Indeed, formation of cervical somites proceeds in Notch1; Notch2-deficient embryos. This is in contrast to mice lacking all presenilin alleles, which have no somites. Since Nicastrin-, Pen-2-, and APH-1a-deficient embryos have anterior somites without gamma-secretase, presenilin may have a gamma-secretase-independent role in somitogenesis. Embryos triple homozygous for both presenilin null alleles and a Notch allele that is a poor substrate for presenilin (N1(V-->G)) experience fortuitous cleavage of N1(V-->G) by another protease. This restores NICD, anterior segmentation, and bilateral symmetry but does not rescue rostral/caudal identities. These data clarify multiple roles for Notch signaling during segmentation and suggest that the earliest stages of somitogenesis are regulated by both Notch-dependent and Notch-independent functions of presenilin.

Amyloid Precursor Protein Secretases↗
PubMed2006

Notch signaling reveals developmental plasticity of Pax4(+) pancreatic endocrine progenitors and shunts them to a duct fate.

Relatively little is known about the developmental signals that specify the types and numbers of pancreatic cells. Previous studies suggested that Notch signaling in the pancreas inhibits differentiation and promotes the maintenance of progenitor cells, but it remains unclear whether Notch also controls cell fate choices as it does in other tissues. To study the impact of Notch in progenitors of the beta cell lineage, we generated mice that express Cre-recombinase under control of the Pax4 promoter. Lineage analysis of Pax4(+) cells demonstrates they are specified endocrine progenitors that contribute equally to four islet cell fates, contrary to expectations raised by the dispensable role of Pax4 in the specification of the alpha and PP subtypes. In addition, we show that activation of Notch in Pax4(+) progenitors inhibits their differentiation into alpha and beta endocrine cells and shunts them instead toward a duct fate. These observations reveal an unappreciated degree of developmental plasticity among early endocrine progenitors and raise the possibility that a bipotent duct-endocrine progenitor exists during development. Furthermore, the redirection of Pax4(+) cells from alpha and beta endocrine fates toward a duct cell type suggests a positive role for Notch signaling in duct specification and is consistent with the more widely defined role for Notch in cell fate determination.

Journal Article↗
PubMed2003

Modeling of ACL impingement against the intercondylar notch.

OBJECTIVE: To develop a 3-D mathematical model that accurately evaluates anterior cruciate ligament impingement against the intercondylar notch. DESIGN: The model simulated physical interactions between the anterior cruciate ligament and the intercondylar notch in tibiofemoral movement. BACKGROUND: Anterior cruciate ligament impingement has been evaluated through planar radiographic images, which may not characterize the complex 3-D notch shape associated with impingement. METHODS: After examining potential anterior cruciate ligament impingement in five cadaver knee specimens, the model was implemented using data from an individual cadaveric knee with representative impingement. The knee was loaded passively in various patterns to induce impingement, and the impingement force and six degrees-of-freedom tibiofemoral kinematics were measured. The femur, tibia, and anterior cruciate ligament were digitized. Spatial data points representing the notch surfaces were surface-fitted using bicubic splines. The model detected for impingement during the tibiofemoral movement and used a "crawling algorithm" to determine the deformed geometry of the impinging ligament. RESULTS: The model detected the impingement accurately and the ligament strain determined by the model was highly correlated with the recorded impingement force when impingement occurred during the tibiofemoral movement. Distance between the anterior cruciate ligament and the notch wall was determined when impingement was not detected. CONCLUSION: The model quantitatively characterized impingement of the anterior cruciate ligament against the intercondylar notch in 3-D space. RELEVANCE: The approach helps us better understand anterior cruciate ligament injury mechanisms in individual knees. Clinically, the model could potentially be used to analyze subject-specific potential/actual anterior cruciate ligament impingement based on the subject's MRI scans.

Anterior Cruciate Ligament↗
PubMed1999

NUMB localizes in the basal cortex of mitotic avian neuroepithelial cells and modulates neuronal differentiation by binding to NOTCH-1.

The importance of lateral inhibition mediated by NOTCH signaling is well demonstrated to control neurogenesis both in invertebrates and vertebrates. We have identified the chicken homolog of Drosophila numb, which suppresses NOTCH signaling. We show that chicken NUMB (c-NUMB) protein is localized to the basal cortex of mitotic neuroepithelial cells, suggesting that c-NUMB regulates neurogenesis by the modification of NOTCH signaling through asymmetrical cell division. Consistent with this suggestion, we show (1) that c-NUMB interferes with the nuclear translocation of activated c-NOTCH-1 through direct binding to the PEST sequence in the cytoplasmic domain of c-NOTCH-1 and (2) that c-NUMB interferes with c-NOTCH-1-mediated inhibition of neuronal differentiation.

Amino Acid Sequence↗
PubMed2002

Glycogen synthase kinase-3beta modulates notch signaling and stability.

Notch receptors modulate transcriptional targets following the proteolytic release of the Notch intracellular domain (NotchIC). Phosphorylated forms of NotchIC have been identified within the nucleus and have been associated with CSL members, as well as correlated with regions of the receptor that are required for activity. Genetic studies have suggested that the Drosophila homolog of glycogen synthase kinase-3beta (GSK3beta), Shaggy, may act as a positive modulator of the Notch signaling. GSK3beta is a serine/threonine kinase and is a component of the Wnt/wingless signaling cascade. Here, we observed that GSK3beta was able to bind and phosphorylate Notch1IC in vitro, and attenuation of GSK3beta activity reduced phosphorylation of NotchIC in vivo. Functionally, ligand-activated signaling through the endogenous Notch1 receptor was reduced in GSK3beta null fibroblasts, implying a positive role for GSK3beta in mammalian Notch signaling. As a possible mechanistic explanation of the effect of GSK3beta on Notch signaling, we observed that inhibition of GSK3beta shortened the half-life of Notch1IC. Conversely, activated GSK3beta reduced the quantity of Notch1IC that was degraded by the proteasome. These studies reveal that GSK3beta modulates Notch1 signaling, possibly through direct phosphorylation of the intracellular domain of Notch, and that the activity of GSK3beta protects the intracellular domain from proteasome degradation.

Animals↗
PubMed2003

Learning and memory deficits in Notch mutant mice.

Notch is a critical component of evolutionarily conserved signaling mechanisms that regulate development and may contribute to plasticity-related processes, including changes in neurite structure and maintenance of neural stem cells. Deficits in the Notch pathway are responsible for Alagille and Cadasil syndromes, which are associated with mental retardation and dementia. Additionally, in postmitotic neurons, Notch proteins interact with presenilins and with beta-amyloid precursor protein and could therefore have a role in the memory deficits associated with familial and sporadic Alzheimer's disease. To test if alterations in Notch signaling can lead to learning and memory deficits, we studied mice with mutations in this pathway. Here, we show that null heterozygous mutations in Notch1 result in deficits in spatial learning and memory without affecting other forms of learning, motor control, or exploratory activity. We also show that null heterozygous mutations in the downstream cofactor RBP-J result in similarly specific spatial learning and memory deficits. These data indicate that a constitutive decrease in Notch signaling can result in specific learning and memory deficits and suggest that abnormalities in Notch-dependent transcription may contribute to the cognitive deficits associated with Alzheimer's disease and Alagille and Cadasil syndromes.

Analysis of Variance↗
PubMed2001

Subversion of the T/B lineage decision in the thymus by lunatic fringe-mediated inhibition of Notch-1.

Notch-1 signaling is essential for lymphoid progenitors to undergo T cell commitment, but the mechanism has not been defined. Here we show that thymocytes ectopically expressing Lunatic Fringe, a modifier of Notch-1 signaling, induce lymphoid progenitors to develop into B cells in the thymus. This cell fate switch resulted from Lunatic Fringe-mediated inhibition of Notch-1 function, as revealed by experiments utilizing lymphoid progenitors in which Notch-1 activity was genetically manipulated. These data identify Lunatic Fringe as a potent regulator of Notch-1 during the T/B lineage decision and show that an important function of Notch-1 in T cell commitment is to suppress B cell development in the thymus.

Animals↗
PubMed2000

Impact of notch filter use on waveforms of First- and Second-Order-Kernel responses from multifocal ERGs.

The filter settings of the amplifier section of ERG recording systems have large impact on the waveforms of the recorded responses. In this study, the effects of a 50 Hz notch filter were assessed for both First-Order-Kernel- (FOK) and Second-Order-Kernel-responses (SOK 1st slice) from multifocal ERGs recorded with a VERIS III system. Amplitude and phase responses of the amplifier section were recorded for typical filter settings with the notch filter active and inactive. Multifocal ERGs (MERGs) from a group of 11 normal subjects were recorded for both amplifier settings, the waveforms resulted from those recordings were compared in the time and frequency domain. To verify the results, the recordings without the notch filter were digitally filtered with a simulated notch filter and compared to the responses recorded with an active analog notch filter. The line filter has the biggest attenuation at 50 Hz with an additional phase jump of 180 degrees. The FOK responses of MERGs are assembled by frequencies below 65 Hz with main spectral components between 19 and 47 Hz. The 1st slice of the SOK consists of frequencies up to 100 Hz with main components between 19 and 84 Hz. Thus, if FOK recordings are to be analyzed, the notch filter of the amplifier can be used in order to cope with noise problems caused by the line frequency of 50 Hz. However, one must be aware that the attenuation of higher frequency components will lead to changes of the waveforms. For SOK analysis, main spectral components are attenuated and/or shifted in phase, which leads to completely different waveforms and severe distortion of the recording results.

Adult↗
PubMed2003

Notch strength insensitivity of self-setting hydroxyapatite bone cements.

The effect of notches on the strength properties of self-setting hydroxyapatite (HA) cements is examined. Such stress concentrators may be present at orthopedic repair sites employing cements and significantly affect their mechanical reliability. Notched tensile specimens were prepared from two cement compositions that resulted in HA and carbonated apatite. The notch radii was varied from 0.15 to 6 mm with a fixed length of 6 mm. The strength of the cements was found to be surprisingly insensitive to the presence of the notches over the range of notch radii examined. A fracture statistics model incorporating a Weibull statistical approach was employed to rationalize the observed notch insensitivity.

Journal Article↗
PubMed2004

The selectivity of neurons in the auditory zone of the mouse midbrain to the direction of movement of a spectral notch in wide-band noise.

A series of noise signals was synthesized with spectral notches whose central frequencies moved regularly along the frequency range (from low frequencies to high and from high frequencies to low), imitating movement of the sound source in the vertical plane. The spike responses of neurons in the inferior colliculus of the mouse (Mus musculus) to noise signals changed as the spectral notch moved relative to the excitatory and inhibitory areas of the receptive fields of the neurons and depended on the notch width. Disinhibition reactions in the inhibitory zones were more marked when a frequency notch in the inhibitory zone was followed by a frequency notch in the excitatory part of the response. It is suggested that the selectivity of neurons to the direction of movement of the spectral notch in a noise signal is based on the interaction of the excitatory and inhibitory inputs. The overall set of neuron responses can provide information on the movement of the sound source in acoustic space.

Acoustic Stimulation↗
PubMed2001

Inactivation of Notch 1 in immature thymocytes does not perturb CD4 or CD8T cell development.

Notch proteins influence cell-fate decisions in many developing systems. Several gain-of-function studies have suggested a critical role for Notch 1 signaling in CD4-CD8 lineage commitment, maturation and survival in the thymus. However, we show here that tissue-specific inactivation of the gene encoding Notch 1 in immature (CD25+CD44-)T cell precursors does not affect subsequent thymocyte development. Neither steady-state numbers nor the rate of production of CD4+ and CD8+ mature thymocytes is perturbed in the absence of Notch 1. In addition, Notch 1-deficient thymocytes are normally sensitive to spontaneous or glucocorticoid-induced apoptosis. In contrast to earlier reports, these data formally exclude an essential role for Notch 1 in CD4-CD8 lineage commitment, maturation or survival.

Animals↗
PubMed2005

Notch signals control the fate of immature progenitor cells in the intestine.

The Notch signalling pathway plays a crucial role in specifying cellular fates in metazoan development by regulating communication between adjacent cells. Correlative studies suggested an involvement of Notch in intestinal development. Here, by modulating Notch activity in the mouse intestine, we directly implicate Notch signals in intestinal cell lineage specification. We also show that Notch activation is capable of amplifying the intestinal progenitor pool while inhibiting cell differentiation. We conclude that Notch activity is required for the maintenance of proliferating crypt cells in the intestinal epithelium.

Animals↗
PubMed1997

The glenoid notch and its relation to the shape of the glenoid cavity of the scapula.

The prevalence of a notch in the anterior margin of the glenoid cavity of 236 scapulae (118 female, 118 male) was investigated. The notch was found in 129 scapulae (55%) and gave rise to a pear-shaped cavity. In 107 scapulae (45%) the notch was absent, the shape of the cavity being oval. No sex difference was found in the prevalence of the notch. If a distinct notch exists, the glenoid labrum is not attached to bone at the notch and is therefore liable to be sheared off (Bankart lesion).

Female↗
PubMed2002

Evaluation of antegonial notch depth for growth prediction.

In recent years, some researchers have proposed that the depth of the mandibular antegonial notch can be used as a predictor of facial growth. However, the data for those studies were derived from populations with extreme morphologic characteristics. The purpose of this investigation was to test the hypothesis that the antegonial notch depth is a useful predictor of facial growth in a longitudinal sample of untreated growing patients selected at random. Lateral cephalometric radiographs were obtained from 20 males and 20 females at 3 times, approximating prepubescence (8.5 years), adolescence (12 years), and adulthood (> or = 17 years). These 40 subjects were randomly chosen from a longitudinal sample of untreated growing patients. Prepubescent and adolescent antegonial notch depths were correlated with vertical and horizontal growth changes of the jaws from the age of 8.5 years to adulthood. Correlation analysis revealed a statistically (but not clinically) significant negative relationship (0.40 < or = r < or = 0.47; P < or =.05) between adolescent antegonial notch depth and horizontal growth of the maxilla and the mandible from adolescence to adulthood. Previous investigators have proposed that antegonial notch depth, when extreme in magnitude, might be used to predict facial growth. We concluded that antegonial notch depth fails to provide sufficient indication of future facial growth to warrant its application as a growth predictor in a nonextreme population.

Adolescent↗
PubMed2005

Notch-1 activation and dendritic atrophy in prion disease.

In addition to neuronal vacuolation and astrocytic hypertrophy, dendritic atrophy is a prominent feature of prion disease. Because increased Notch-1 expression and cleavage releasing its intracellular domain (NICD) inhibit both dendrite growth and maturation, we measured their levels in brains from mice inoculated with Rocky Mountain Laboratory (RML) prions. The level of NICD was elevated in the neocortex, whereas the level of beta-catenin, which stimulates dendritic growth, was unchanged. During the incubation period, levels of the disease-causing prion protein isoform, PrPSc, and NICD increased concomitantly in the neocortex. Additionally, increased levels of Notch-1 mRNA and translocation of NICD to the nucleus correlated well with regressive dendritic changes. In scrapie-infected neuroblastoma (ScN2a) cells, the level of NICD was elevated compared with uninfected control (N2a) cells. Long neurofilament protein-containing processes extended from the surface of N2a cells, whereas ScN2a cells had substantially shorter processes. Transfection of ScN2a cells with a Notch-1 small interfering RNA decreased Notch-1 mRNA levels, diminished NICD concentrations, and rescued the long process phenotype. These results suggest that PrPSc in neurons and in ScN2a cells activates Notch-1 cleavage, resulting in atrophy of dendrites in the CNS and shrinkage of processes on the surface of cultured cells. Whether diminishing Notch-1 activation in vivo can prevent or even reverse neurodegeneration in prion disease remains to be established.

Active Transport, Cell Nucleus↗
PubMed2001

Repression of activator protein-1-mediated transcriptional activation by the Notch-1 intracellular domain.

Developmental decisions that control cell fate are commonly regulated by the Notch signaling pathway. Activation of transmembrane Notch receptors results in proteolytic liberation of the intracellular domain of Notch, which translocates into the nucleus, binds a repressor (C promoter binding factor 1/RBP-Jkappa, Su(H), and Lag-1 (CSL)), and induces target genes. We found that the intracellular domain of human Notch-1 (NIC-1) represses activator protein-1 (AP-1)-mediated transactivation. Because numerous genes that control immune and inflammatory responses are AP-1-dependent and Notch regulates immune cell function, we investigated the underlying molecular mechanisms. Repression of AP-1 by NIC-1 did not represent a general inhibitory effect on transcription because nuclear factor kappaB-dependent transcription and transcription driven by a constitutive promoter and enhancer were not affected by NIC-1. The physiological relevance of the repression was supported by the facts that repression was apparent in multiple cell lines, endogenous AP-1 target genes were repressed, and similar concentrations of NIC-1 were required for CSL-dependent activation and AP-1 repression. The RBP-Jkappa-associated molecule domain of NIC-1 that mediates CSL binding and distinct sequences necessary for transactivation were required for repression. However, there was not a strict correlation between the sequence requirements for CSL-dependent activation and AP-1 repression. Repression correlated with predominant nuclear localization of NIC-1 and was not accompanied by disruption of c-Jun amino-terminal kinase-dependent signaling events required for AP-1 activation or by defective AP-1 DNA binding activity. These results provide evidence for negative cross-talk between Notch and AP-1, which may have important consequences for controlling diverse biological processes.

Amino Acid Sequence↗
PubMed2002

The human acid alpha-glucosidase gene is a novel target of the Notch-1/Hes-1 signaling pathway.

Acid alpha-glucosidase (GAA) is a lysosomal enzyme that degrades glycogen. A deficiency of GAA is responsible for a recessively inherited myopathy and cardiomyopathy, glycogenosis type II. Previously, we identified an intronic repressor element in the GAA gene and demonstrated that Hes-1, a basic helix-loop-helix factor, binds to a C class E box within the element and functions as a transcriptional repressor in HepG2 cells. Hes-1 is a well studied downstream target gene in the Notch signaling pathway. In this study, over-expression and depletion of Notch-1 intracellular domain (NICD) strategies were used to investigate whether expression of the GAA gene is under the control of Notch-1/Hes-1 signaling. In co-transfection experiments, Hes-1, up-regulated by over-expressed NICD, enhanced the repressive effect of the DNA element with wild type Hes-1 binding sites but not with mutant Hes-1 binding sites. Conversely, depletion of Notch-1 with phosphorothioated antisense oligonucleotides, corresponding to the fourth ankyrin repeat within NICD, led to reduced Hes-1. Constitutively over-expressed Hes-1 and Notch-1 repressed GAA gene expression. Therefore, our data establish that the human GAA gene, encoding a lysosomal enzyme, is a downstream target of the Notch-1/Hes-1 signaling pathway.

Base Sequence↗
PubMed2003

The anti-apoptotic effect of Notch-1 requires p56lck-dependent, Akt/PKB-mediated signaling in T cells.

The Notch family of transmembrane receptors have been implicated in a variety of cellular decisions in different cell types. Here we investigate the mechanism underlying Notch-1-mediated anti-apoptotic function in T cells using model cell lines as the experimental system. Ectopic expression of the intracellular domain of Notch-1/activated Notch (AcN1) increases expression of anti-apoptotic proteins of the inhibitors of apoptosis (IAP) family, the Bcl-2 family, and the FLICE-like inhibitor protein (FLIP) and inhibits death triggered by multiple stimuli that activate intrinsic or extrinsic pathways of apoptosis in human and murine T cell lines. Numb inhibited the AcN1-dependent induction of anti-apoptotic proteins and anti-apoptotic function. Using pharmacological inhibitors and dominant-negative approaches, we describe a functional role for phosphatidylinositol 3-kinase (PI3K)-dependent activation of the serine-threonine kinase Akt/PKB in the regulation of AcN1-mediated anti-apoptotic function and the expression of FLIP and IAP family proteins. Using a cell line deficient for the T cell-specific, Src family protein, the tyrosine kinase p56(lck) and by reconstitution approaches we demonstrate that p56(lck) is required for the Notch-1-mediated activation of Akt/PKB function. Furthermore, the Src tyrosine kinase inhibitor, PP2, abrogated ectopically expressed AcN1-mediated anti-apoptotic function and phosphorylation of p56(lck). We present evidence that endogenous Notch-1 associates with p56(lck) and PI3K but that Akt/PKB does not co-immunoprecipitate with the Notch1.p56(lck).PI3K complex. Finally, we demonstrate that the Notch1.p56(lck).PI3K complex is present in primary T cells that have been activated in vitro and sustained in culture with the cytokine interleukin-2.

Apoptosis↗