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PubMedDate not supplied

Expression of the p63 and Notch signaling systems in rat testes during postnatal development: comparison with their expression levels in the epididymis and vas deferens.

The role of tubular structures that contribute to the passage of spermatozoa is not solely passive; these structures actively contribute to their own functions, although these tubules and ducts are contiguous and collaborate in the development of the male gamete along their lengths. The testis has the specific function to generate spermatozoa and spermatozoa undergo numerous changes as they pass through the epididymis. A member of the p53 family of genes, p63, is highly expressed in the basal layers of epithelial tissues and plays a key role in maintaining their cell populations, whereas Notch 1 and its ligand Jagged 2 have an important role in the differentiation of germ cells and Jagged 2 is up-regulated by TAp63, one of the p63 isoforms, which transactivates p53 target genes and induces apoptosis. Although the presence of p63 in most epithelia is established, the role of p63 and its possible relationship with the Notch system in the seminiferous epithelium have not been examined. Therefore, we investigated the expression of p63, Jagged 2, and Notch 1 in the testis during postnatal development in comparison with their expression levels in the vaso-epididymal epithelium. In the testis, the expression of TAp63 mRNA increased at day 14 after birth and the expressions of Jagged 2 and Notch 1 mRNA increased at day 16 after birth, suggesting that TAp63-mediated Jagged 2 induction activates the Notch signaling system. On the other hand, the strong signal of DeltaNp63 mRNA was already recognized in the vas deferens at day 0 after birth and advanced chronologically along the duct to the caput epididymis and p63 protein was expressed in basal cells in their epithelium, whereas the mRNAs of Jagged 2 and Notch 1 were maintained at a low level. Consequently, examination of our data raises the probability that TAp63 has an important role for maintenance of germ cell numbers, triggering or balancing the development, differentiation, and apoptosis of germ cells in the testis, which is completely different from the role of DeltaNp63 in other epithelial tissues.

Animals↗
PubMed2006

Physiology and pathology of notch signalling system.

Notch proteins encode a family of transmembrane receptors that are part of a signalling transduction system known as Notch signalling, an extremely conserved and widely used mechanism regulating programs governing growth, apoptosis and differentiation in metazoans. Notch signalling begins when the Notch receptor binds ligands and ends when the Notch intracellular domain enters the nucleus and activates transcription of target genes. This core pathway is subjected to a wide array of regulatory influences and protein-protein interactions and is correlated with other signalling pathway. This review will summarize recent findings concerning the physiology and pathology of Notch signalling in vascular development and homeostasis. Moreover, the clinical phenotypes of Notch3 signalling system pathology will be described, with particular regard to CADASIL (Cerebral Autosomal Dominant Arteriopathy with Subcortical Infarcts and Leukoencephalopathy) for which the most recent pathogenetic hypotheses are reported.

Animals↗
PubMed2003

Regulation of ganglion cell production by Notch signaling during retinal development.

Although progenitor cells in developing vertebrate retina are capable of producing all retinal cell types, they are competent to produce only certain cell types at a given time, and this competence changes as development progresses. We asked whether a change in progenitor cell competence is primarily responsible for ending production of a specific cell type, the retinal ganglion cell. Reducing Notch expression using an antisense oligonucleotide in vitro or in vivo increased ganglion cell genesis. The antisense treatment could reinitiate ganglion cell genesis after it had terminated in a region of the retina, but only for a brief period. The failure of the Notch antisense treatment to reinitiate ganglion cell production after this period was not due to the lack of receptor or ligand expression, as both Notch-1 and Delta-1 were still expressed. The failure of the Notch antisense treatment to reinitiate ganglion cell production is consistent with the suggestion that the intrinsic competence of progenitor cells changes as development progresses. Because reducing Notch signaling can reinitiate ganglion cell production for a brief period after ganglion cell production has normally ceased, it appears that ganglion cell production initially ends in a region of the retina because of cell-cell interactions and not because progenitor cells lose the competence to make ganglion cells. Notch signaling appears to temporarily prevent production of ganglion cells in a region, while some other signal must initiate a change in progenitor cell competence, thus permanently ending the possibility of further ganglion cell production.

Animals↗
PubMed2004

The role of Notch receptor expression in bile duct development and disease.

Mutations in the Jagged1 gene, a ligand for the Notch signalling pathway, have been implicated in the pathogenesis of Alagille syndrome (AGS), resulting in bile duct paucity. Recently, a mouse model for AGS suggested that abnormalities of the Notch2 receptor, as well as of Jagged1, may be present. Expression patterns of Notch receptors have not been described in the developing human liver or in paediatric liver. The expression of Notch receptors and ligands was examined in fetal, paediatric normal, and diseased human liver by RT-PCR and immunohistochemistry. RT-PCR showed Notch1-4 mRNA expression to be present. In fetal liver, Notch3 protein was expressed on mesenchymal cells, closely adjacent to ductal plate cells that expressed Jagged1. In paediatric normal liver, Notch1 and Notch2 were present on mature bile duct cells. Notch expression was altered in disease, with distinct differences in AGS from extrahepatic biliary atresia (EHBA) and alpha1-anti-trypsin deficiency (alpha1AT). In AGS, where extensive ductular reaction was present, Jagged1 was expressed on ductular reactive cells (DRCs), along with marked Notch2 and Notch3 staining. Where there was ductular paucity, Notch2 and Notch3 were not expressed on remaining biliary epithelial cells. In EHBA and alpha1AT, Notch receptor expression was not seen on DRCs. Instead, Notch2 and Notch3 were expressed by stromal cells. In all diseases, Notch3 was expressed on neovessels in portal tracts and cirrhotic fibrous septa. In conclusion, Notch3 is expressed in close proximity to Jagged1 at the time of ductal plate formation, suggesting that Notch3 is important for bile duct development. The expression of both Notch2 and Notch3 in AGS on DRCs confirms that these receptors may be important in the pathogenesis of this disease. Further studies are required to investigate the presence of Notch2 and Notch3 at other periods in liver development and to clarify the role of Notch signalling in paediatric cholestases.

Adolescent↗
PubMed1994

Delta-notch signaling and Drosophila cell fate choice.

Delta and Notch encode cell surface proteins that function in a wide variety of cell fate specification events during oogenesis, embryogenesis, and metamorphosis in Drosophila melanogaster. Various lines of evidence imply that Delta and Notch proteins function as signal and receptor in cellular interactions required for the partitioning of fates among cells within equivalence groups in many developmental contexts. Molecular and genetic observations provide a framework for the formulation of hypotheses concerning the mechanisms by which the Delta ligand and Notch receptor interact and the Delta-Notch signal is transduced in a manner that can affect the adoption of distinct fates by different cells. In particular, emerging evidence regarding the expression and function of Delta and Notch during development also raise possible alternatives to the currently favored hypothesis that Delta-Notch interactions generate instructive signals that mediate a process termed lateral inhibition.

Animals↗
PubMed1998

Multiple roles for notch in Drosophila myogenesis.

Notch plays a role in many cell fate decisions in the developing Drosophila embryo, often at successive stages during the formation of a single tissue. In the embryonic mesoderm, Notch is involved in the process by which muscle progenitors are selected from a field of equivalent myoblasts. We have investigated the roles of Notch in somatic myogenesis and show that Notch can affect at least two additional steps in muscle development. Subsequent to the initial specification of progenitors, myoblast identity remains sensitive to mesodermal Notch activity until the time of fusion. Additionally, Notch is capable of suppressing muscle development nonautonomously by regulating a signal that emanates from the ectoderm.

Animals↗
PubMed1998

Delta-notch signaling in odontogenesis: correlation with cytodifferentiation and evidence for feedback regulation.

Recent data suggest that dental cells utilize the evolutonarily conserved Notch-mediated intercellular signaling pathway to regulate their fates. Here we report on the expression and regulation of Delta1, a transmembrane ligand of the Notch receptors, during mouse odontogenesis. Delta1 is weakly expressed in dental epithelium during tooth initiation and morphogenesis, but during cytodifferentiation, expression is upregulated in the epithelium-derived ameloblasts and the mesenchyme-derived odontoblasts. The expression pattern of Delta1 in ameloblasts and odontoblasts is complementary to Notch1, Notch2, and Notch3 expression in adjacent epithelial and mesenchymal cells. Notch1 and Notch2 are upregulated in explants of dental mesenchyme adjacent to implanted cells expressing Delta1, suggesting that feedback regulation by Delta-Notch signaling ensures the spatial segregation of Notch receptors and ligands. TGFbeta1 and BMPs induce Delta1 expression in dental mesenchyme explants at the stage at which Delta1 is upregulated in vivo, but not at earlier stages. In contrast to the Notch family receptors and their ligand Jagged1, expression of Delta1 in the tooth germ is not affected by epithelial-mesenchymal interactions, showing that the Notch receptors and their two ligands Jagged1 and Delta1 are subject to different regulations.

Animals↗
PubMed1999

Notch-mediated segmentation and growth control of the Drosophila leg.

The possession of segmented appendages is a defining characteristic of the arthropods. By analyzing both loss-of-function and ectopic expression experiments, we show that the Notch signaling pathway plays a fundamental role in the segmentation and growth of the Drosophila leg. Local activation of Notch is necessary and sufficient to promote the formation of joints between segments. This segmentation process requires the participation of the Notch ligands, Serrate and Delta, as well as Fringe. These three proteins are each expressed in the developing leg and antennal imaginal discs in a segmentally repeated pattern that is regulated downstream of the action of Wingless and Decapentaplegic. Our studies further show that Notch activation is both necessary and sufficient to promote leg growth. We also identify target genes regulated both positively and negatively downstream of Notch signaling that are required for normal leg development. Together, these observations outline a regulatory hierarchy for the segmentation and growth of the leg. The Notch pathway is also deployed for segmentation during vertebrate somitogenesis, which raises the possibility of a common origin for the segmentation of these distinct tissues.

Aging↗
PubMed2001

The Nrarp gene encodes an ankyrin-repeat protein that is transcriptionally regulated by the notch signaling pathway.

We have identified a gene encoding a novel protein that is transcriptionally regulated by the Notch signaling pathway in mammals. This gene, named Nrarp (for Notch-regulated ankyrin-repeat protein), encodes a 114 amino acid protein that has a unique amino-terminus and a carboxy-terminal domain containing two ankyrin-repeat motifs. A Xenopus homolog of the Nrarp gene was previously identified in a large-scale in situ hybridization screen of randomly isolated cDNA clones. We demonstrate that in T-cell and myoblast cell lines expression of the Nrarp gene is induced by the intracellular domain of the Notch1 protein, and that this induction is mediated by a CBF1/Su(H)/Lag-1 (CSL)-dependent pathway. During mouse embryogenesis, the Nrarp gene is expressed in several tissues in which cellular differentiation is regulated by the Notch signaling pathway. Expression of the Nrarp gene is downregulated in Notch1 null mutant mouse embryos, indicating that expression of the Nrarp gene is regulated by the Notch pathway in vivo. Thus, Nrarp transcript levels are regulated by the level of Notch1 signaling in both cultured cell lines and mouse embryos. During somitogenesis, the Nrarp gene is expressed in a pattern that suggests that Nrarp expression may play a role in the formation of somites, and Nrarp expression in the paraxial mesoderm is altered in several Notch pathway mutants that exhibit defects in somite formation. These observations demonstrate that the Nrarp gene is an evolutionarily conserved transcriptional target of the Notch signaling pathway.

Alleles↗
PubMed1999

Reactivation of Delta-Notch signaling after injury: complementary expression patterns of ligand and receptor in dental pulp.

The evolutionarily conserved Notch-mediated intercellular signaling pathway is essential for proper embryonic development of many tissues and organs. Recent data suggest that Notch receptors and their membrane-bound ligands Delta and Serrate are involved in both patterning and cell fate determination during odontogenesis. It remains, however, uncertain if Notch signaling is important for tooth homeostasis and regeneration. Here we report on the expression of Notch receptors and the Delta1 ligand in dental pulp of normal and injured adult rat teeth. Notch receptors were absent from normal adult dental tissues, whereas expression was upregulated after injury. In injured teeth, Notch2 was expressed in mesenchymal cells of the pulp both close to the site of injury (i.e., in the dental crown) and at a distance from it (i.e., in the dental roots), Notch3 expression was mainly associated with vascular structures, while Notch1 expression was restricted to few pulpal cells close to the lesion. None of them was expressed in odontoblasts. Expression of Delta1 was upregulated in odontoblasts of the injured teeth, as well as in vascular structures. These results demonstrate the reactivation of the Notch signaling pathway during wound healing and, furthermore, highlight the similarity between developmental and regenerative processes.

Animals↗
PubMed1998

Structural conservation of Notch receptors and ligands.

The Notch signalling pathway is an evolutionarily conserved cell-to-cell communication system utilized multiple times and in many tissues during development. The outcome of an interaction between Notch and its ligands is highly influenced by factors both extrinsic and intrinsic to Notch expressing cells, suggesting that Notch functions either directly or in parallel with other signalling systems to regulate cellular differentiation events. Protein domains common to all ligands and receptors of this system suggest conserved functional properties that likely relate to regulatory mechanisms for Notch signalling. Within this review, the known functional properties of these domains are analyzed with respect to their contributions to ligand/receptor interactions and Notch signalling.

Amino Acid Sequence↗
PubMed1998

Modulators of Notch signaling.

In addition to the core components of the Notch pathway, a number of proteins have been identified that exert positive or negative influences on Notch signaling. These include extracellular modulators, which may influence binding or activation of Notch by its ligands, cytoplasmic modulators, which presumably influence signal transduction steps after receptor activation, and nuclear modulators, which may influence the transcriptional activity of a Notch-CSL protein complex. Many of the cytoplasmic and nuclear modulators appear to bind directly to discrete domains within the intracellular domain of Notch. Genetic studies indicate that distinct modulators are deployed during distinct modes of Notch signaling.

Animals↗
PubMed2001

Evolutionary analysis of vertebrate Notch genes.

We have conducted an evolutionary analysis of Notch genes of the vertebrates Danio rerio and Mus musculus to examine the expansion and diversification of the Notch family during vertebrate evolution. The existence of multiple Notch genes in vertebrate genomes suggests that the increase in Notch signaling pathways may be necessary for the additional complexity observed in the vertebrate body plan. However, orthology relationships within the vertebrate Notch family indicate that biological functions are not fixed within orthologous groups. Phylogenetic reconstruction of the vertebrate Notch family suggests that the zebrafish notch1a and 1b genes resulted from a duplication occurring around the time of the teleost/mammalian divergence. There is also evidence that the mouse Notch4 gene is the result of a rapid divergence from a Notch3-like gene. Investigation of the ankyrin repeat region sequences showed there to be little evidence for gene conversion events between repeat units. However, relationships between repeats 2-5 suggest that these repeats are the result of a tandem duplication of a dual repeat unit. Selective pressure on maintenance of ankyrin repeat sequences indicated by relationships between the repeats suggests that specific repeats are responsible for particular biological activities, a finding consistent with mutational studies of the Caenorhabditis elegans gene glp-1. Sequence similarities between the ankyrin repeats and the region immediately C-terminal of the repeats further suggests that this region may be involved in the modulation of ankyrin repeat function.

Amino Acid Sequence↗
PubMed1994

The suppressor of hairless protein participates in notch receptor signaling.

In a genetic screen for mutations that attenuate Notch signaling in the developing Drosophila eye, we isolated rare, gain-of-function alleles of Suppressor of Hairless (Su(H)), the fly homolog of the mammalian C promoter-binding factor 1 (CBF1) gene. Su(H) exhibits numerous allele-specific genetic interactions with Notch as well as with Delta, deltex, and mastermind. In cultured Drosophila cells, the Su(H) protein is sequestered in the cytoplasm when coexpressed with Notch protein and is translocated to the nucleus when Notch binds to its ligand Delta. Cytoplasmic retention of Su(H) requires the intracellular cdc10/ankyrin repeats of Notch, which associate with Su(H) protein in the yeast interaction trap assay. These results indicate that Notch activity may regulate nuclear events by controlling the activity of a DNA-binding protein.

Amino Acid Sequence↗
PubMed1995

Drosophila eye development: Notch and Delta amplify a neurogenic pattern conferred on the morphogenetic furrow by scabrous.

Loss of function mutations of scabrous and conditional alleles of Notch and Delta affect the pattern of morphogenetic furrow development. By studying differentiation of R8 cells, the first photoreceptor neuron subtype to differentiate, we show that all furrow cells pass through an R8-competent stage. Function of Notch and scabrous is necessary if most of these cells are to attain other cell fates. The scabrous gene confers a regular pattern on the morphogenetic furrow, restricting R8 differentiation to alternating groups of cells. Notch and Delta function to restrict the R8 fate to a single cell in each group. Without scabrous gene function, action of Notch and Delta on the entire morphogenetic furrow results in a disorganised pattern of ommatidia arising from a disorganised array of single R8 cells. Aspects of the scabrous mutant phenotype also suggest a secondary role in selecting a single R8 cell from competent clusters. We show that scabrous expression preceeds changes in the apical profiles of morphogenetic furrow cells that identify ommatidial precurf1p4cells, and also preceeds changes in levels of Notch and Delta expression. The pattern of initiation of sca expression depends on sca gene function, indicating that patterning of the morphogenetic furrow depends on the pattern of posterior columns. Our results suggest that in the eye, Notch and Delta amplify and refine a morphogenetic landscape generated by scabrous. Cell determination in other tissues and organisms might also be molded in a two-step process where initial inhomogeneities determined by one protein provide a context for subsequent development.

Animals↗
PubMed1996

Expression of the Notch 3 intracellular domain in mouse central nervous system progenitor cells is lethal and leads to disturbed neural tube development.

Notch-like receptors are found in organisms ranging from nematodes to mammals. In Drosophila, Notch plays a key role in cell fate decisions in the early nervous system. In this report we analyse the effects of excess Notch 3 activity in central nervous system (CNS) progenitor cells. A mutated Notch gene encoding the intracellular domain of mouse Notch 3 transcribed from the nestin promoter was expressed in CNS progenitor cells in transgenic mice. This mutation resulted in a phenotypic series of neural tube defects in embryonic day 10.5-12.5 embryos and proved lethal to embryos beyond this age. In the milder phenotype the neural tube displayed a zig-zag morphology and the CNS was slightly enlarged. More severely affected embryos showed a lack of closure of the anterior neural pore, resulting in the externalization of neural tissue and the complete collapse of the third and fourth ventricles. The expanded ventricular zone of the neuroepithelium, a correspondingly enlarged area of nestin expression, and an increase in the number of proliferating cells in the neural tube suggested that these phenotypes resulted from an expanded CNS progenitor cell population. These data provide support in vivo for the notion that Notch activity plays a role in mammalian CNS development and may be required to guide CNS progenitor cells in their choice between continued proliferation or neuronal differentiation.

Animals↗
PubMed2004

Notch signaling: the demise of elegant simplicity.

Notch signaling can be viewed as an elegantly simple pathway that begins when the Notch receptor binds ligand, and ends when the Notch intracellular domain enters the nucleus and activates transcription. However, it is becoming increasingly clear that this core pathway is subject to a wide array of regulatory influences, from those that affect ligand-receptor interactions to those that govern the choice of Notch target genes. Even Notch ligands are now being scrutinized with respect to the possibility that they, too, function in the nucleus. A complete understanding of Notch signaling therefore requires us to look well beyond the core pathway.

Animals↗
PubMed2006

Stage-specific and differential notch dependency at the alphabeta and gammadelta T lineage bifurcation.

Signals transduced by Notch receptors are indispensable for T cell specification and differentiation of alphabeta T lineage cells. However, the role of Notch signals during alphabeta versus gammadelta T lineage decision remains controversial. Here, we addressed this question by employing a clonal analysis of CD4(-)CD8(-) (DN) progenitor potential to position the divergence of alphabeta and gammadelta T cell lineages to the late DN2 to DN3 developmental stages. Accordingly, alphabeta and gammadelta precursor frequencies within these T cell progenitor subsets were determined, both in the presence and absence of Notch signaling through Delta-like 1. Notch signals were found to be critical for the DN to CD4(+)CD8(+) (DP) transition, irrespective of the identity (pTalphabeta or gammadelta) of the inducing T cell receptor complex, whereas gammadelta T cells developed from gammadeltaTCR-expressing T cell progenitors in the absence of further Notch ligand interaction. Collectively, our findings demonstrate a differential, stage-specific requirement for Notch receptor-ligand interactions in the differentiation of alphabeta and gammadelta T cells from T cell progenitors.

Animals↗