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PubMed2005

[Japanese CADASIL case with limited dementia who had the Notch 3 R141C mutation].

Cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is a rare hereditary disease characterized by recurrent transient ischemic attacks (TIA) and strokes, and vascular dementia caused by point mutations of the Notch 3 gene. Here, we report a Japanese CADASIL case who displayed limited dementia and had the Notch 3 R141C mutation. The relationship between pathogenesis and the mutation site in Notch 3 is discussed based on the case presented here.

CADASIL↗
PubMed2005

Inhibitors of gamma-secretase block in vivo and in vitro T helper type 1 polarization by preventing Notch upregulation of Tbx21.

Notch receptors are processed by gamma-secretase acting in synergy with T cell receptor signaling to sustain peripheral T cell activation. Activated CD4+ T cells differentiate into T helper type 1 (TH1) or TH2 subsets. Molecular cues directing TH1 differentiation include expression of the TH1-specific transcription factor T-bet, encoded by Tbx21. However, the regulation of Tbx21 remains incompletely defined. Here we report that Notch1 can directly regulate Tbx21 through complexes formed on the Tbx21 promoter. In vitro, gamma-secretase inhibitors extinguished expression of Notch, interferon-gamma and Tbx21 in TH1-polarized CD4+ cells, whereas ectopic expression of activated Notch1 restored Tbx21 transcription. In vivo, administration of gamma-secretase inhibitors substantially impeded TH1-mediated disease progression in the mouse experimental autoimmune encephalomyelitis model of multiple sclerosis. Thus, using gamma-secretase inhibitors to modulate Notch signaling may prove beneficial in treating TH1-mediated autoimmunity.

Amyloid Precursor Protein Secretases↗
PubMedDate not supplied

Finite element analysis of the stress-concentrating effect of fraenal notches in complete dentures.

Based on clinical experience and empiricism, it was postulated that fraenal notches and midline diastemas lead to fracture of complete dentures. This study used finite element stress analysis to investigate the stress-concentrating effect of a fraenal notch with and without a midline diastema. It was found that a large fraenal notch resulted in high stress levels and that these stresses were augmented more by a narrow median diastema than its wider counterpart.

Dental Stress Analysis↗
PubMed1987

Origin of notches in CSF: optical or neural?

Grating contrast sensitivity was measured across a range of 1 to 32 cycles per degree (c/deg) in normal observers with a computer-automated method of ascending limits. Monocular contrast sensitivity functions (CSF) were obtained for vertical, oblique and horizontal orientations, with or without full refractive correction. Small amounts of astigmatic error resulted in loss of sensitivity at selective spatial frequencies. Coincident with these CSF "notches" was the presence of monocular diplopia induced, in this study, by the condition of astigmatic error. Experimental manipulation of the selective spatial frequency losses was possible by the introduction of slight cylindrical defocus and by changes in grating orientation. Determination of the angular displacement and orientation of the monocular double images allowed prediction of the spatial frequencies which would show reduced sensitivity due to partial cancellation of contrast. The close fit between the predicted and measured sensitivity loss supports the suggestion that refractive error can affect narrowly-tuned notches. These results indicate that before the presence of a notch in the CSF can be attributed to neural abnormality, an optical cause must be eliminated.

Adult↗
PubMed1978

Greater sciatic notch in sex determination.

Various measurements of the greater sciatic notch, e.g. width, depth and length of the posterior segment (of width) were measured, and indices I and II calculated, in 200 adult hip bones (120 males and 80 females). Total and posterior angles were measured after construction of a triangle from the above measurements in each case. Demarking points for sexing of hip bones were calculated for the above seven parameters on the lines of Jit & Singh (1966). Width and depth of the greater sciatic notch were found to be useless criteria for sexing purposes while the posterior angle was found to be the best parameter, which identified 75% of left and 88% of right male hip bones and 92% of left and 100% of right female bones. Length of the posterior segment and Index II also assigned sex to a high percentage of hip bones, especially to the female ones (95-97%), which suggests that the widening of the greater sciatic notch found in females has occurred primarily in its posterior part. The demarking points identify sex with 100% accuracy.

Anthropometry↗
PubMedDate not supplied

Suprascapular nerve entrapment. A report of two cases treated with suprascapular notch resection.

Suprascapular nerve entrapment occurs in the shoulder after a severe forward flexing injury (hyperprotraction) because of tethering of the nerve in the scapular notch. Unrelenting pain in this shoulder region is relieved by section of the transverse scapular ligament in most cases. Two patients, reported here, had temporary relief from simple transverse scapular ligament release and later lasting relief of pain from scapular notch resection. These observations suggest that primary wide notch resection may be the preferable procedure.

Female↗
PubMed2026

Multidimensional Proteomics Reveals the Pro-apoptotic Mechanism of Platycodin D: Targeting RFC4 to Regulate the Notch Signaling Axis in Non-Small Cell Lung Cancer.

Platycodin D (PD), a major bioactive saponin isolated from the traditional Chinese medicine Platycodon grandiflorus, has shown promising therapeutic potential against non-small cell lung cancer (NSCLC). However, the functional mechanisms of PD in NSCLC progression remains unclear. This study aimed to explore the pharmacological mechanism of PD against NSCLC. Thermal proteome profiling approach, molecular docking, cellular thermal shift assay and peptide-centric local stability assay were employed to identify the potential binding target of PD. Subsequent Western Blot and immunoprecipitation-Western Blot experiments were conducted to investigate the downstream signaling pathways of the target. Furthermore, proteomic and ubiquitinomic profiling of PD-treated cells were performed to investigate its functions on global. replication factor C subunit 4 (RFC4) was identified as a potential binding target of PD by thermal proteome profiling and their binding sites were further exposed by peptide-centric local stability assay. PD-RFC4 complex promotes the degradation of Notch1 and Notch3 by reducing nuclear entry of their domains. Compared with control treatment, the differentially expressed proteins induced by PD were found to be primarily involved in ferroptosis, ubiquitination, platinum drug resistance, and ribosome-related processes. The ubiquitin proteome analysis revealed that proteins associated with the Notch pathway underwent ubiquitin modifications. PD binds to RFC4 and inhibits its activity, leading to downregulation of the Notch signaling pathway, ultimately triggering cancer cell apoptosis. PD is a natural product with potential therapeutic value for NSCLC.

Saponins↗
PubMed2005

Fjx1: a notch-inducible secreted ligand with specific binding sites in developing mouse embryos and adult brain.

The mouse fjx1 gene was identified as a homologue to the Drosophila gene four-jointed (fj). Fj encodes a transmembrane type II glycoprotein that is partially secreted. The gene was found to be a downstream target of the Notch signaling pathway in leg segmentation and planar cell polarity processes during eye development of Drosophila. Here, we show that fjx1 is not only conserved in vertebrates, but we also identified the murine fjx1 gene as a direct target of Notch signaling. In addition to the previously described expression of fjx1 in mouse brain, we show here that fjx1 is expressed in the peripheral nervous system, epithelial cells of multiple organs, and during limb development. The protein is processed and secreted as a presumptive ligand. Through the use of an fjx1-AP fusion protein, we could visualize fjx1 binding sites at complementary locations, supporting the notion that fjx1 may function as a novel signaling molecule.

Aging↗
PubMed2005

Regulation of Tbx6 expression by Notch signaling.

Somites are the first overt sign of segmentation in the vertebrate embryo and form from bilateral strips of paraxial mesoderm. Paraxial mesoderm arises from the primitive streak; it then migrates laterally and comes to lie on both sides of the neural tube. In the mouse, the T-box transcription factor Tbx6 is required for both somite formation and patterning. Tbx6 expression corresponds both temporally and spatially to somite formation, with expression in the primitive streak and presomitic mesoderm. Its expression in the latter could simply be explained by maintenance following its initial activation in the primitive streak. Alternatively, its expression in the presomitic mesoderm may be contributed by separate regulatory elements possibly under the control of different signals. We have begun to investigate how Tbx6 expression is controlled during development using a transgenic approach to identify the cis-acting regulatory regions. We show that it is possible to separate an element required for presomitic mesoderm expression from that driving expression in the primitive streak. Further, we show that a binding site for the Notch transcription factor RBP-Jkappa is necessary for Tbx6 presomitic mesoderm enhancer activity, indicating that Notch signaling is upstream of Tbx6 in the pathway directing somite formation and patterning.

Animals↗
PubMed2005

Amyloid precursor protein interacts with notch receptors.

The amyloid precursor protein (APP) must fulfill important roles based on its sequence conservation from fly to human. Although multiple functions for APP have been proposed, the best-known role for this protein is as the precursor of Abeta peptide, a neurotoxic 39-43-amino acid peptide crucial to the pathogenesis of Alzheimer's disease. To investigate additional roles for APP with an eye toward understanding the molecular basis of the pleiotropic effects ascribed to APP, we isolated proteins that interacted with the plasma membrane isoform of APP. We employed a membrane-impermeable crosslinker to immobilize proteins binding to transmembrane APP in human embryonic kidney (HEK)293 cells expressing APP751 (HEK275) or rat embryonic day 18 primary neurons infected with a virus expressing APP. Notch2 was identified as a potential APP binding partner based on mass spectrometry analysis of APP complexes immunopurified from neurons. To confirm the interaction between Notch2 and APP, we carried out immunoprecipitation studies in HEK275 cells transiently expressing full-length Notch2 using Notch2 antibodies. The results indicated that APP and Notch2 interact in mammalian cells, and confirmed our initial findings. Interestingly, Notch1 also coimmunoprecipitated with APP, suggesting that APP and Notch family members may engage in intermolecular cross talk to modulate cell function. Finally, cotransfection of APP/CFP and Notch2/YFP into COS cells revealed that these two proteins colocalize on the plasma membrane. Intracellularly, however, although some APP and Notch molecules colocalize, others reside in distinct locations. The discovery of proteins that interact with APP may aid in the identification of new functions for APP.

Amyloid beta-Protein Precursor↗
PubMed1998

Different spatial and temporal interactions between Notch, wingless, and vestigial specify proximal and distal pattern elements of the wing in Drosophila.

The wing of Drosophila is composed of a proximal element, the hinge, which attaches it to the thorax, and a distal one, the wing blade. The development of the wing is a complex process that requires the integration of cellular responses to two signaling systems centered along the anteroposterior and the dorsoventral axes. The genes Notch (N) and wingless (wg) play an important role in generating the information from the dorsoventral axis. The vestigial (vg) gene is necessary for the development of the wing and is a target of these signaling systems during the growth of the wing. Here we examine the roles that N, wg, and vg play during the initial stages of wing development. Our results reveal that vg is involved in the specification of the wing primordium under the combined control of Notch and wingless signaling. Furthermore, we show that once cells are assigned to the wing fate, their development relies on a sequence of regulatory loops that involve N, wg, and vg. During this process, cells that are exposed to the activity of both wg and vg will become wing blade and those that are continuously under the influence of wg alone will develop as hinge. Our results also indicate that the growth of the cells in the wing blade results from a synergistic effect of the three genes N, wg, and vg on the cells that have been specified as wing blade.

Animals↗
PubMed2002

Lunatic fringe, FGF, and BMP regulate the Notch pathway during epithelial morphogenesis of teeth.

Teeth develop as epithelial appendages, and their morphogenesis is regulated by epithelial-mesenchymal interactions and conserved signaling pathways common to many developmental processes. A key event during tooth morphogenesis is the transition from bud to cap stage when the epithelial bud is divided into specific compartments distinguished by morphology as well as gene expression patterns. The enamel knot, a signaling center, forms and regulates the shape and size of the tooth. Mesenchymal signals are necessary for epithelial patterning and for the formation and maintenance of the epithelial compartments. We studied the expression of Notch pathway molecules during the bud-to-cap stage transition of the developing mouse tooth. Lunatic fringe expression was restricted to the epithelium, where it formed a boundary flanking the enamel knot. The Lunatic fringe expression domains overlapped only partly with the expression of Notch1 and Notch2, which were coexpressed with Hes1. We examined the regulation of Lunatic fringe and Hes1 in cultured explants of dental epithelium. The expression of Lunatic fringe and Hes1 depended on mesenchymal signals and both were positively regulated by FGF-10. BMP-4 antagonized the stimulatory effect of FGF-10 on Lunatic fringe expression but had a synergistic effect with FGF-10 on Hes1 expression. Recombinant Lunatic fringe protein induced Hes1 expression in the dental epithelium, suggesting that Lunatic fringe can act also extracellularly. Lunatic fringe mutant mice did not reveal tooth abnormalities, and no changes were observed in the expression patterns of other Fringe genes. We conclude that Lunatic fringe may play a role in boundary formation of the enamel knot and that Notch-signaling in the dental epithelium is regulated by mesenchymal FGFs and BMP.

Animals↗
PubMed1996

Epithelial expression and chromosomal location of human TLE genes: implications for notch signaling and neoplasia.

The TLE genes are the human homologues of Drosophila groucho, a member of the Notch signaling pathway. This pathway controls a number of different cell-fate choices in invertebrates and vertebrates. We are interested in investigating the functions of the TLE gene family during epithelial determination and carcinogenesis. We show that expression of individual TLE genes correlates with immature epithelial cells that are progressing toward their terminally differentiated state, suggesting a role during epithelial differentiation. In both normal tissues and conditions resulting from incorrect or incomplete maturation events, such as metaplastic and neoplastic transformations, TLE expression is elevated and coincides with Notch expression, implicating these molecules in the maintenance of the undifferentiated state in epithelial cells. We also show that TLE1 and TLE2 are organized in a tandem array at chromosomal location 19p13.3, while TLE3 maps to 15q22.

Animals↗
PubMed1998

Notch signalling in Drosophila: three ways to use a pathway.

Cell-cell interactions mediated by Notch are critical at multiple stages of development. Our current understanding of the Notch signalling pathway suggests a comparatively simple transduction mechanism. However, this core pathway can be deployed in three different types of developmental process: lateral inhibition, lineage decisions and boundary formation. These illustrate how the activity of the pathway can be modulated both at the cell surface, through availability and effectiveness of ligand interactions, and inside the cell, through effects on the transduction pathway and the responsiveness of target genes.

Animals↗
PubMed2005

Temporal expression of Notch in preterm rat lungs exposed to hyperoxia.

To explore the mechanism of Notch in hyperoxia-induced preterm rat lung injury, 2-days-old preterm SD rats were randomized into control and hyperoxia group (FiO2 > or = 0.85). On day 1, 7, 14 and 21, 8 rat pups of each time point were used to assess histopathological changes of lung with HE staining and to evaluate the expression of Notch1 and Notch3 with immunohistochemistry. Notch1, Notch3, Aquaprin5 (AQP5) and surfactant protein C (SP-C) mRNA were measured by reverse transcription polymerase chain reaction (RT-PCR). The results showed that the lung injury in the hyperoxia group was characterized by retarded lung alveolization and differentiation of alveolar epithelial type II cells (AEC II). Positive staining of Notch1 in hyperoxia group was weaker than controls at every time point (except for day 7), while positive staining of Notch3 was much stronger (P < 0.05, P < 0.01). Notch1, Notch3 mRNA level showed similar change as protein level. AQP5, SP-C mRNA decreased significantly as compared with that of the controls (P < 0.01). We are led to conclude that hyperoxia results in abnormal expression of Notch, which is likely to contribute to the pathogenesis of lung injury through regulating proliferation and transdifferentiation of alveolar epithelial cells.

Aerobiosis↗
PubMed1999

Disturbance of Notch-1 and Wnt signalling proteins in neuroglial balloon cells and abnormal large neurons in focal cortical dysplasia in human cortex.

Determination of neuroglial cell fate and neural tube development during embryogenesis is influenced by the Notch/Wnt signalling pathway. We have studied the localisation of several proteins in the Wnt pathway in focal cortical dysplasia (FCD). This disorder, thought to be due to abnormalities of neuronal migration and differentiation, contains regions of morphologically normal neocortex interrupted by areas of neuronal laminar disorganisation, heterotopic white matter neurons, abnormal large neurons and balloon cells of uncertain histogenesis. We found that the subcellular distribution of several proteins involved in the Wnt pathway differed in regions of FCD from normal cortex, and that within the areas of FCD, the pattern varied with cellular phenotype. Thus, in balloon cells, elevated cytoplasmic levels of dishevelled (Dvl-1) protein were accompanied by an absence of Notch-1, increased adenomatous poliposis coli (APC), altered cytoplasmic beta-catenin, and reduced nuclear expression of beta-catenin. A contrasting pattern of expression was found in abnormal large neurons, which demonstrated elevated levels of Notch-1, and glycogen synthase kinase-3beta (GSK-3beta), and normal levels of APC. Our results are consistent with the notion that Wnt/Notch signalling influences neuroglial cell fate, and suggest that a perturbation of Wnt/Notch signalling may contribute to the neuropathology of FCD.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Isolation of adult murine thymic stromal cells that naturally express Notch ligands.

This communication summarizes the procedures that enabled isolation of adult murine thymic stromal cell lines that naturally express Notch ligands Jagged-1 or Delta-1. Histochemical characterization of these cell lines, in terms of ligand and cell type, revealed epithelial cells that bear an antigen characteristic of the thymic medulla and express either Jagged-1 or Delta-1. FACS sorting of stromal cells that naturally express these and other ligands is thus feasible, and such cells can be used to investigate the activity of each ligand in Notch-mediated commitment to the T-lymphocyte pathway.

Animals↗
PubMed2003

A genomewide survey of developmentally relevant genes in Ciona intestinalis. V. Genes for receptor tyrosine kinase pathway and Notch signaling pathway.

In the present survey, we identified most of the genes involved in the receptor tyrosine kinase (RTK), mitogen activated protein kinase (MAPK) and Notch signaling pathways in the draft genome sequence of Ciona intestinalis, a basal chordate. Compared to vertebrates, most of the genes found in the Ciona genome had fewer paralogues, although several genes including ephrin, Eph and fringe appeared to have multiplied or duplicated independently in the ascidian genome. In contrast, some genes including kit/flt, PDGF and Trk receptor tyrosine kinases were not found in the present survey, suggesting that these genes are innovations in the vertebrate lineage or lost in the ascidian lineage. The gene set identified in the present analysis provides an insight into genes for the RTK, MAPK and Notch signaling pathways in the ancient chordate genome and thereby how chordates evolved these signaling pathway.

Animals↗