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PubMed1997

The Notch ligand, X-Delta-2, mediates segmentation of the paraxial mesoderm in Xenopus embryos.

Segmentation of the vertebrate embryo begins when the paraxial mesoderm is subdivided into somites, through a process that remains poorly understood. To study this process, we have characterized X-Delta-2, which encodes the second Xenopus homolog of Drosophila Delta. Strikingly, X-Delta-2 is expressed within the presomitic mesoderm in a set of stripes that corresponds to prospective somitic boundaries, suggesting that Notch signaling within this region establishes a segmental prepattern prior to somitogenesis. To test this idea, we introduced antimorphic forms of X-Delta-2 and Xenopus Suppressor of Hairless (X-Su(H)) into embryos, and assayed the effects of these antimorphs on somite formation. In embryos expressing these antimorphs, the paraxial mesoderm differentiated normally into somitic tissue, but failed to segment properly. Both antimorphs also disrupted the segmental expression of X-Delta-2 and Hairy2A, a basic helix-loop-helix (bHLH) gene, within the presomitic mesoderm. These observations suggest that X-Delta-2, via X-Notch-1, plays a role in segmentation, by mediating cell-cell interactions that underlie the formation of a segmental prepattern prior to somitogenesis.

Animals↗
PubMed1998

A new role for Notch and Delta in cell fate decisions: patterning the feather array.

Chick embryonic feather buds arise in a distinct spatial and temporal pattern. Although many genes are implicated in the growth and differentiation of the feather buds, little is known about how the discrete pattern of the feather array is formed and which gene products may be involved. Possible candidates include Notch and its ligands, Delta and Serrate, as they play a role in numerous cell fate decisions in many organisms. Here we show that Notch-1 and Notch-2 mRNAs are expressed in the skin in a localized pattern prior to feather bud initiation. In the early stages of feather bud development, Delta-1 and Notch-1 are localized to the forming buds while Notch-2 expression is excluded from the bud. Thus, Notch and Delta-1 are expressed at the correct time and place to be players in the formation of the feather pattern. Once the initial buds form, expression of Notch and its ligands is observed within each bud. Notch-1 and -2 and Serrate-1 and -2 are expressed throughout the growth and differentiation of the feathers whereas Delta-1 transcripts are downregulated. We have also misexpressed chick Delta-1 using a replication competent retrovirus. This results in induction of Notch-1 and-2 and a loss of feather buds from the embryo in either large or small patches. In large regions of Delta-1 misexpression, feathers are lost throughout the infected area. In contrast, in small regions of misexpression, Delta-1 expressing cells differentiate into feather buds more quickly than normal and inhibit their neighbors from accepting a feather fate. We propose a dual role for Delta-1 in promoting feather bud development and in lateral inhibition. These results implicate the Notch/Delta receptor ligand pair in the formation of the feather array.

Animals↗
PubMed1999

Wnt-7a in feather morphogenesis: involvement of anterior-posterior asymmetry and proximal-distal elongation demonstrated with an in vitro reconstitution model.

How do vertebrate epithelial appendages form from the flat epithelia? Following the formation of feather placodes, the previously radially symmetrical primordia become anterior-posterior (A-P) asymmetrical and develop a proximo-distal (P-D) axis. Analysis of the molecular heterogeneity revealed a surprising parallel of molecular profiles in the A-P feather buds and the ventral-dorsal (V-D) Drosophila appendage imaginal discs. The functional significance was tested with an in vitro feather reconstitution model. Wnt-7a expression initiated all over the feather tract epithelium, intensifying as it became restricted first to the primordia domain, then to an accentuated ring pattern within the primordia border, and finally to the posterior bud. In contrast, sonic hedgehog expression was induced later as a dot within the primordia. RCAS was used to overexpress Wnt-7a in reconstituted feather explants derived from stage 29 dorsal skin to further test its function in feather formation. Control skin formed normal elongated, slender buds with A-P orientation, but Wnt-7a overexpression led to plateau-like skin appendages lacking an A-P axis. Feathers in the Wnt-7a overexpressing skin also had inhibited elongation of the P-D axes. This was not due to a lack of cell proliferation, which actually was increased although randomly distributed. While morphogenesis was perturbed, differentiation proceeded as indicated by the formation of barb ridges. Wnt-7a buds have reduced expression of anterior (Tenascin) bud markers. Middle (Notch-1) and posterior bud markers including Delta-1 and Serrate-1 were diffusely expressed. The results showed that ectopic Wnt-7a expression enhanced properties characteristic of the middle and posterior feather buds and suggest that P-D elongation of vertebrate skin appendages requires balanced interactions between the anterior and posterior buds.

Animals↗
PubMed1999

The notch 3 intracellular domain represses notch 1-mediated activation through Hairy/Enhancer of split (HES) promoters.

The Notch signaling pathway is important for cellular differentiation. The current view is that the Notch receptor is cleaved intracellularly upon ligand activation. The intracellular Notch domain then translocates to the nucleus, binds to Suppressor of Hairless (RBP-Jk in mammals), and acts as a transactivator of Enhancer of Split (HES in mammals) gene expression. In this report we show that the Notch 3 intracellular domain (IC), in contrast to all other analysed Notch ICs, is a poor activator, and in fact acts as a repressor by blocking the ability of the Notch 1 IC to activate expression through the HES-1 and HES-5 promoters. We present a model in which Notch 3 IC interferes with Notch 1 IC-mediated activation at two levels. First, Notch 3 IC competes with Notch 1 IC for access to RBP-Jk and does not activate transcription when positioned close to a promoter. Second, Notch 3 IC appears to compete with Notch 1 IC for a common coactivator present in limiting amounts. In conclusion, this is the first example of a Notch IC that functions as a repressor in Enhancer of Split/HES upregulation, and shows that mammalian Notch receptors have acquired distinct functions during evolution.

Animals↗
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↗
PubMed2001

An instructive function for Notch in promoting gliogenesis in the zebrafish retina.

The Gal4-UAS technique has been used to misexpress a constitutively active Notch receptor variant (notch1a-intra) in the developing zebrafish retina. This is the first study to use this technique to misexpress genes and assess their function in neural development of the zebrafish. Expression of activated Notch1a either ubiquitously, driven by a heat-shock70 promoter, or in a spatially regulated manner, controlled by the deltaD promoter, causes a block in neuronal differentiation that affects all cell types. Developing cells take on either a glial fate or remain undifferentiated. A large number of cells eventually undergo apoptosis. These phenotypic effects of activated Notch1a are expressed cell autonomously. Cells within central regions of the retina adopt a glial fate if they express activated Notch1a in a time window that extends from 27 to 48 hours postfertilization. This period corresponds mainly to the time of origin of ganglion cells in the normal retina. Activation of notch1a at later stages results in defects in cell type specification that remain restricted to the ciliary marginal zone, whereas neuronal types are specified normally within the central region. These observations indicate that glial differentiation is initiated by Notch1a-intra expressing cells, which become postmitotic in the same time window. Our results strongly suggest that Notch1a instructs a certain cell population to enter gliogenesis, and keeps the remaining cells in an undifferentiated state. Some or all of these cells will eventually succumb to apoptosis.

Animals↗
PubMed2002

Bimodal functions of Notch-mediated signaling are involved in neural crest formation during avian ectoderm development.

Neural crest is induced at the junction of epidermal ectoderm and neural plate by the mutual interaction of these tissues. In previous studies, BMP4 has been shown to pattern the ectodermal tissues, and BMP4 can induce neural crest cells from the neural plate. In this study, we show that epidermally expressed Delta1, which encodes a Notch ligand, is required for the activation and/or maintenance of Bmp4 expression in this tissue, and is thus indirectly required for neural crest induction by BMP4 at the epidermis-neural plate boundary. Notch activation in the epidermis additionally inhibits neural crest formation in this tissue, so that neural crest generation by BMP4 is restricted to the junction.

Animals↗
PubMed2002

her1 and the notch pathway function within the oscillator mechanism that regulates zebrafish somitogenesis.

Somite formation is thought to be regulated by an unknown oscillator mechanism that causes the cells of the presomitic mesoderm to activate and then repress the transcription of specific genes in a cyclical fashion. These oscillations create stripes/waves of gene expression that repeatedly pass through the presomitic mesoderm in a posterior-to-anterior direction. In both the mouse and the zebrafish, it has been shown that the notch pathway is required to create the stripes/waves of gene expression. However, it is not clear if the notch pathway comprises part of the oscillator mechanism or if the notch pathway simply coordinates the activity of the oscillator among neighboring cells. In the zebrafish, oscillations in the expression of a hairy-related transcription factor, her1 and the notch ligand deltaC precede somite formation. Our study focuses on how the oscillations in the expression of these two genes is affected in the mutants aei/deltaD and des/notch1, in 'morpholino knockdowns' of deltaC and her1 and in double 'mutant' combinations. This analysis indicates that these oscillations in gene expression are created by a genetic circuit comprised of the notch pathway and the notch target gene her1. We also show that a later function of the notch pathway can create a segmental pattern even in the absence of prior oscillations in her1 and deltaC expression.

Animals↗
PubMed2004

The surface of articular cartilage contains a progenitor cell population.

It is becoming increasingly apparent that articular cartilage growth is achieved by apposition from the articular surface. For such a mechanism to occur, a population of stem/progenitor cells must reside within the articular cartilage to provide transit amplifying progeny for growth. Here, we report on the isolation of an articular cartilage progenitor cell from the surface zone of articular cartilage using differential adhesion to fibronectin. This population of cells exhibits high affinity for fibronectin, possesses a high colony-forming efficiency and expresses the cell fate selector gene Notch 1. Inhibition of Notch signalling abolishes colony forming ability whilst activated Notch rescues this inhibition. The progenitor population also exhibits phenotypic plasticity in its differentiation pathway in an embryonic chick tracking system, such that chondroprogenitors can engraft into a variety of connective tissue types including bone, tendon and perimysium. The identification of a chondrocyte subpopulation with progenitor-like characteristics will allow for advances in our understanding of both cartilage growth and maintenance as well as provide novel solutions to articular cartilage repair.

Amyloid Precursor Protein Secretases↗
PubMed2000

Murine Delta homologue, mDelta1, expressed on feeder cells controls cellular differentiation.

The Delta/Serrate-Notch pathway is involved in intercellular signaling that controls cell fate during the development of invertebrates and vertebrates. Delta is a prototype of Notch ligands and has been studied extensively in Drosophila. In higher vertebrates, four Delta/Serrate homologues and four Notch homologues have been identified. Recent studies showed that the murine Delta homologue, mDelta1, is essential in early embryogenesis. The biological activity of mammalian Delta and its roles in cellular differentiation, however, have remained unclear. In this study, we first surveyed expression of mDelta1 in the adult mouse and found it to be present in a wide range of tissues. For testing biological activity of mDelta1, we expressed a mDelta1 full-length cDNA in L cells using a eukaryotic expression vector. Effects of mDelta1 on cellular differentiation were examined in two independent systems, featuring C2C12 myogenic differentiation and multipotent murine bone marrow cell differentiation. Inhibition of the former was observed with mDelta1 expression on L cells, associated with suppression of myogenin, a myogenic transcription factor. Expression of mDelta1 in conjunction with GM-CSF promoted differentiation of bone marrow cells to myeloid dendritic cells at the expense of other lineages. Although the effects of mDelta1 on two differentiation systems appeared opposing, as inhibition occurring in one and induction in the other, this can be understood by the unifying concept of generation of diverse cell types from equivalent progenitors. Thus, the present study provided evidence that mammalian Delta participates in intercellular signaling, determining the cell fate in a wide variety of tissues.

Animals↗
PubMed2000

[Understanding of molecular pathogenesis of Alzheimer's disease: implications for drug development].

Recent advances in the knowledge about Alzheimer pathogenesis indicate several tactics for the development of drugs to treat Alzheimer's disease. Firstly, the function of presenilin, the causative gene for most familial Alzheimer's disease, has been demonstrated to be the protease in the Notch signaling system. Presenilin cleaves the transmembrane domain of the C-terminal fragment of the Notch-1 molecule, which is generated by proteolysis by furin-like proteases. APP is also cleaved by presenilin at the gamma cut site, implying that presenilin is gamma-secretase itself or at least closely functioning with gamma-secretase. A recent paper has demonstrated that immunization of APP transgenic mouse with amyloid beta 42 may decrease and prevent amyloid deposition in brain tissue. This unique and novel approach may open the new tactics for developing anti-dementia drugs. Another important finding comes from the identification of the function of prolyl isomerase. It is demonstrated that pin 1, intra-nuclear prolyl isomerase, can restore the microtubule binding capacity of phosphorylated tau, which clearly shows a solid strategy for developing drugs for preventing neuronal degeneration.

Alzheimer Disease↗
PubMed2004

The Saccharomyces cerevisiae TAN1 gene is required for N4-acetylcytidine formation in tRNA.

The biogenesis of transfer RNA is a process that requires many different factors. In this study, we describe a genetic screen aimed to identify gene products participating in this process. By screening for mutations lethal in combination with a sup61-T47:2C allele, coding for a mutant form of, the nonessential TAN1 gene was identified. We show that the TAN1 gene product is required for formation of the modified nucleoside N(4)-acetylcytidine (ac(4)C) in tRNA. In Saccharomyces cerevisiae, ac(4)C is present at position 12 in tRNAs specific for leucine and serine as well as in 18S ribosomal RNA. Analysis of RNA isolated from a tan1-null mutant revealed that ac(4)C was absent in tRNA, but not rRNA. Although no tRNA acetyltransferase activity by a GST-Tan1 fusion protein was detected, a gel-shift assay revealed that Tan1p binds tRNA, suggesting a direct role in synthesis of ac(4)C(12). The absence of the TAN1 gene in the sup61-T47:2C mutant caused a decreased level of mature, indicating that ac(4)C(12) and/or Tan1p is important for tRNA stability.

Chromatography, High Pressure Liquid↗
PubMed2001

Implication of APP secretases in notch signaling.

Signaling via notch receptors and their ligands is an evolutionary ancient and highly conserved mechanism governing cell-fate decisions throughout the animal kingdom. Upon ligand binding, notch receptors are subject to a two-step proteolysis essential for signal transduction. First, the ectodomain is removed by an enzyme cleaving near the outer-membrane surface ("site2"). Consecutively, the notch intracellular domain is liberated by a second protease cutting within the transmembrane sequence ("site3"). The intracellular domain is then transferred to the nucleus to act as a transcriptional coactivator. The proteases involved in notch receptor activation are shared with other proteins undergoing regulated intramembrane proteolysis, with intriguing parallels to APP. Specifically, site3 cleavage of Notch, as well as gamma-secretase processing of APP depend both critically on presenilins 1 and 2. Moreover, ADAM 10 and ADAM 17, the proteases proposed to perform site2 cleavage, are also the most probable candidate alpha-secretases to cleave APP. While the biological significance of APP processing remains to be further elucidated, interference with notch signaling has been shown to have severe consequences both in small animal models as well as in humans. Thus, a growing number of long known genetic syndromes like Alagille syndrome or Fallot's tetralogy can be caused by mutations of genes relevant for the notch signaling pathway. Likewise, the anticipated interference of gamma-secretase inhibitors with site3 cleavage may turn out to be a major obstacle for this therapeutic approach to Alzheimer's disease.

ADAM Proteins↗
PubMed2001

Nuclear signaling: a common function of presenilin substrates?

Major progress has recently been made in the characterization of the secretases involved in endoproteolytic processing of the Alzheimer's disease (AD)-associated beta-amyloid precursor protein, betaAPP. betaAPP is the precursor of the amyloid beta-peptide, which is a major constituent of amyloid plaques in the brains of Alzheimer patients. It is now commonly believed that Abeta plays a pivotal role in the pathogenesis of AD, and that inhibiting the production of Abeta may help to treat or to prevent the disease. With beta-secretase and the presenilins, two essential factors in the proteolytic generation of Abeta have now been identified. However, very little is still known about the biological function of the long-known betaAPP. In this review we will discuss a novel putative function of betaAPP in nuclear signaling, an activity, that betaAPP may share with other presenilin substrates such as Notch.

Acetyltransferases↗
PubMed2003

Molecular mechanisms that regulate auditory hair-cell differentiation in the mammalian cochlea.

Mechanosensory hair cells of the vertebrate cochlea offer an excellent developmental system to study cell-fate specification, and to gain insight into the many human neurological deficits which result in a hearing loss, by affecting primarily the hair cells. Therefore, there is great interest in studying the molecular mechanisms that regulate their specification and differentiation. Recent studies, based mostly on loss-of-function experiments that target the role of Notch signaling and basic helix-loop-helix genes in inner-ear development have indicated that they can regulate mechanosensory hair cell-fate specification and their initial differentiation.

Animals↗
PubMed2004

Peroxisome-proliferator-activated receptor gamma induces a clearance mechanism for the amyloid-beta peptide.

We investigated whether peroxisome proliferator-activated receptor gamma (PPARgamma) could be involved in the modulation of the amyloid cascade causing Alzheimer's disease. Inducing expression or activating PPARgamma using synthetic agonists of the thiazolinedione family results in a dramatic decrease in the levels of the amyloid-beta (Abeta) peptide in the conditioned medium of neuronal and non-neuronal cells. PPARgamma does not affect expression or activity of any of the secretases involved in the generation of the Abeta peptide but induces a fast, cell-bound clearing mechanism responsible for the removal of the Abeta peptide from the medium. Although PPARgamma expression is generally low in the CNS, induction of PPARgamma expression during inflammation could be beneficial for inducing Abeta clearance. We confirm that the Abeta clearance mechanism can indeed be induced by PPARgamma activation in primary murine-mixed glia and cortical neuronal cultures. Our results suggest that PPARgamma-controlled mechanisms should be explored further as potential drug targets for Alzheimer's disease treatment.

Amyloid Precursor Protein Secretases↗
PubMed2005

Regulation of acquired immune system by notch signaling.

T- and B-cells are generated from hematopoietic stem cells through lymphoid intermediates. The interplay of intrinsic and extrinsic signals determines cell fate at the branch point for T- and B-cell lineages and at the post-commitment stage of lymphogenesis. The mature lymphocytes differentiate into effector/memory cells by antigen recognition, and those differentiation steps are also governed by a series of cell fate choices and survival signals, which allows cells to acquire distinct effector functions. The identification of the molecular details that dictate lymphocyte development and differentiation will improve understanding of acquired immune responses. Recent studies have revealed that Notch molecules, evolutionarily conserved transmembrane receptors, play key roles in lymphocyte development and differentiation. In this article, we review recent knowledge regarding the roles of Notch signaling in controlling both lymphocyte development and acquisition of effector functions.

Animals↗
PubMed2004

The possible correlation of Notch-1 and Notch-2 with clinical outcome and tumour clinicopathological parameters in human breast cancer.

The Notch-1 and Notch-2 receptors play crucial roles in cell fate determination through interaction with the Delta/Serrate/Lag-2 family of ligands. The function of Notch signalling in tumourigenesis is still unclear, however, reports have demonstrated unregulated Notch activity in a variety of human cancers. We quantified Notch-1 and Notch-2 expression, in association with clinical outcome, in tissue samples from breast cancer patients (normal specimens n=24, breast cancer specimens n=97). We used qualitative and quantitative RT-PCR analysis, along with immunohistochemical staining to examine Notch-1 and Notch-2 expression in association with the patients clinical parameters (median follow-up 72 months). Our results show that there are aberrant levels of Notch-1 and Notch-2 in breast cancer tissues compared with normal breast tissue. Examination of the breast cancer patients' clinicopathological parameters reported that a high level of Notch-1 may be associated with a poorer outlook for the breast cancer patient, while a high level of Notch-2 correlated to a higher chance of survival. Notch-1 and Notch-2 also appear to play crucial and contrasting roles in breast tumour differentiation. Notch-1 expression was low in grade 1 tumours and increased in poorly-differentiated tumours, whereas, Notch-2 expression was high in well-differentiated tumours and reduced in breast tumours with poor differentiation. Therefore, Notch-1 may possess tumour-promoting functions, while Notch-2 could play a tumour-suppressive role in human breast cancer. These results support the notion that suppression of Notch-1 activity may represent a novel therapeutic strategy.

Base Sequence↗