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PubMed2006

Cross-platform expression profiling demonstrates that SV40 small tumor antigen activates Notch, Hedgehog, and Wnt signaling in human cells.

BACKGROUND: We previously analyzed human embryonic kidney (HEK) cell lines for the effects that simian virus 40 (SV40) small tumor antigen (ST) has on gene expression using Affymetrix U133 GeneChips. To cross-validate and extend our initial findings, we sought to compare the expression profiles of these cell lines using an alternative microarray platform. METHODS: We have analyzed matched cell lines with and without expression of SV40 ST using an Applied Biosystems (AB) microarray platform that uses single 60-mer oligonucleotides and single-color quantitative chemiluminescence for detection. RESULTS: While we were able to previously identify only 456 genes affected by ST with the Affymetrix platform, we identified 1927 individual genes with the AB platform. Additional technical replicates increased the number of identified genes to 3478 genes and confirmed the changes in 278 (61%) of our original set of 456 genes. Among the 3200 genes newly identified as affected by SV40 ST, we confirmed 20 by QRTPCR including several components of the Wnt, Notch, and Hedgehog signaling pathways, consistent with SV40 ST activation of these developmental pathways. While inhibitors of Notch activation had no effect on cell survival, cyclopamine had a potent killing effect on cells expressing SV40 ST. CONCLUSIONS: These data show that SV40 ST expression alters cell survival pathways to sensitize cells to the killing effect of Hedgehog pathway inhibitors.

Antigens, Polyomavirus Transforming↗
PubMed2004

Math1 controls cerebellar granule cell differentiation by regulating multiple components of the Notch signaling pathway.

Cerebellar granule cells (CGC) are the most abundant neurons in the mammalian brain, and an important tool for unraveling molecular mechanisms underlying neurogenesis. Math1 is a bHLH transcription activator that is essential for the genesis of CGC. To delineate the effects of Math1 on CGC differentiation, we generated and studied primary cultures of CGC progenitors from Math1/lacZ knockout mice. Rhombic lip precursors appeared properly positioned, expressed CGC-specific markers, and maintained Math1 promoter activity in vivo and in vitro, suggesting that Math1 is not essential for the initial stages of specification or survival of CGC. Moreover, the continuous activity of Math1 promoter in the absence of MATH1, indicated that MATH1 was not necessary for the activation of its own expression. After 6, but not 3, days in culture, Math1 promoter activity was downregulated in control cultures, but not in cells from Math1 null mice, thus implying that Math1 participates in a negative regulatory feedback loop that is dependent on increased levels of MATH1 generated through the positive autoregulatory feedback loop. In addition, Math1 null CGC did not differentiate properly in culture, and were unable to extend processes. All Notch signaling pathway receptors and ligands tested were expressed in the rhombic lip at embryonic date 14, with highest levels of Notch2 and Jag1. However, Math1-null rhombic lip cells presented conspicuous downregulation of Notch4 and Dll1. Moreover, of the two transcriptional repressors known to antagonize Math1, Hes5 (but not Hes1) was downregulated in Math1-null rhombic lip tissue and primary cultures, and was shown to bind MATH1, thus revealing a negative regulatory feedback loop. Taken together, our data demonstrate that CGC differentiation, but not specification, depends on Math1, which acts by regulating the level of multiple components of the Notch signaling pathway.

Animals↗
PubMed2004

Histone deacetylase 1 is required to repress Notch target gene expression during zebrafish neurogenesis and to maintain the production of motoneurones in response to hedgehog signalling.

Histone deacetylases (Hdacs) are widely implicated as key components of transcriptional silencing mechanisms. Here, I show that hdac1 is specifically required in the zebrafish embryonic CNS to maintain neurogenesis. In hdac1 mutant embryos, the Notch-responsive E(spl)-related neurogenic gene her6 is ectopically expressed at distinct sites within the developing CNS and proneural gene expression is correspondingly reduced or eliminated. Using an hdac1-specific morpholino, I show that this requirement for hdac1 is epistatic to the requirement for Notch signalling. Consequently, hdac1-deficient embryos exhibit several defects of neuronal specification and patterning, including a dramatic deficit of hedgehog-dependent branchiomotor neurones that is refractory to elevated levels of hedgehog signalling. Thus, in the zebrafish embryo, hdac1 is an essential component of the transcriptional silencing machinery that supports the formation and subsequent differentiation of neuronal precursors.

Animals↗
PubMed2004

her3, a zebrafish member of the hairy-E(spl) family, is repressed by Notch signalling.

her3 encodes a zebrafish bHLH protein of the Hairy-E(Spl) family. During embryogenesis, the gene is transcribed exclusively in the developing central nervous system, according to a fairly simple pattern that includes territories in the mesencephalon/rhombencephalon and the spinal cord. In all territories, the her3 transcription domain encompasses regions in which neurogenin 1 (neurog1) is not transcribed, suggesting regulatory interactions between the two genes. Indeed, injection of her3 mRNA leads to repression of neurog1 and to a reduction in the number of primary neurones, whereas her3 morpholino oligonucleotides cause ectopic expression of neurog1 in the rhombencephalon. Fusions of Her3 to the transactivation domain of VP16 and to the repression domain of Engrailed show that Her3 is indeed a transcriptional repressor. Dissection of the Her3 protein reveals two possible mechanisms for transcriptional repression: one mediated by the bHLH domain and the C-terminal WRPW tetrapeptide; and the other involving the N-terminal domain and the orange domain. Gel retardation assays suggest that the repression of neurog1 transcription occurs by binding of Her3 to specific DNA sequences in the neurog1 promoter. We have examined interrelationships of her3 with members of the Notch signalling pathway by the Gal4-UAS technique and mRNA injections. The results indicate that Her3 represses neurog1 and, probably as a consequence of the neurog1 repression, deltaA, deltaD and her4. Moreover, Her3 represses its own transcription as well. Surprisingly, and in sharp contrast to other members of the E(spl) gene family, transcription of her3 is repressed rather than activated by Notch signalling.

Animals↗
PubMed2004

Localized Notch signal acts through eyg and upd to promote global growth in Drosophila eye.

Notch (N) signal is activated at the dorsoventral (DV) border of the Drosophila eye disc and is important for growth of the eye disc. In this study, we showed that the Pax protein Eyg is a major effector mediating the growth promotion function of N. eyg transcription is induced by N signaling occurring at the DV border. Like N, eyg controls growth of the eye disc. Loss of N signaling can be compensated by overexpressing eyg, whereas loss of the downstream eyg blocked the function of N signaling. In addition, we showed that N and eyg could induce expression of upd, which encodes the ligand for the Jak/STAT pathway and acts over long distance to promote cell proliferation. Loss of eyg or N can be compensated by overexpressing upd. These results suggest that upd is a major effector mediating the function of eyg and N. The functional link from N to eyg to upd explains how the localized Notch activation can achieve global growth control.

Animals↗
PubMed2004

Drosophila Epsin mediates a select endocytic pathway that DSL ligands must enter to activate Notch.

Recent findings suggest that Delta/Serrate/Lag2 (DSL) signals activate Notch by an unprecedented mechanism that requires the ligands to be endocytosed in signal-sending cells to activate the receptor in signal-receiving cells. Here, we show that cells devoid of Epsin, a conserved adaptor protein for Clathrin-mediated endocytosis, behave normally except that they cannot send DSL signals. Surprisingly, we find that Epsin is not required for bulk endocytosis of DSL proteins. Instead, Epsin appears to be essential for targeting DSL proteins to a special endocytic pathway that they must enter to acquire signaling activity. We present evidence that DSL proteins must be mono-ubiquitinated to be targeted by Epsin to this pathway. Furthermore, we show that the requirements for both Epsin and mono-ubiquitination can be bypassed by introducing the internalization signal that mediates endocytosis and recycling of the Low Density Lipoprotein (LDL) receptor. We propose that Epsin is essential for DSL signaling because it targets mono-ubiquitinated DSL proteins to an endocytic recycling compartment that they must enter to be converted into active ligands. Alternatively Epsin may be required to target mono-ubiquitinated DSL proteins to a particular subclass of coated pits that have special properties essential for Notch activation.

Adaptor Proteins, Vesicular Transport↗
PubMed2004

Delta proteins and MAGI proteins: an interaction of Notch ligands with intracellular scaffolding molecules and its significance for zebrafish development.

Delta proteins activate Notch through a binding reaction that depends on their extracellular domains; but the intracellular (C-terminal) domains of the Deltas also have significant functions. All classes of vertebrates possess a subset of Delta proteins with a conserved ATEV* motif at their C termini. These ATEV Deltas include Delta1 and Delta4 in mammals and DeltaD and DeltaC in the zebrafish. We show that these Deltas associate with the membrane-associated scaffolding proteins MAGI1, MAGI2 and MAGI3, through a direct interaction between the C termini of the Deltas and a specific PDZ domain (PDZ4) of the MAGIs. In cultured cells and in subsets of cells in the intact zebrafish embryo, DeltaD and MAGI1 are co-localized at the plasma membrane. The interaction and the co-localization can be abolished by injection of a morpholino that blocks the mRNA splicing reaction that gives DeltaD its terminal valine, on which the interaction depends. Embryos treated in this way appear normal with respect to some known functions of DeltaD as a Notch ligand, including the control of somite segmentation, neurogenesis, and hypochord formation. They do, however, show an anomalous distribution of Rohon-Beard neurons in the dorsal neural tube, suggesting that the Delta-MAGI interaction may play some part in the control of neuron migration.

Animals↗
PubMed2005

The Notch-target gene hairy2a impedes the involution of notochordal cells by promoting floor plate fates in Xenopus embryos.

We have previously shown that the early Xenopus organiser contains cells equally potent to give rise to notochord or floor plate, and that Notch signalling triggers a binary decision, favouring the floor plate fate at the expense of the notochord. Now, we present evidence that Delta1 is the ligand that triggers the binary switch, which is executed through the Notch-mediated activation of hairy2a in the surrounding cells within the organiser, impeding their involution through the blastopore and promoting their incorporation into the hairy2a+ notoplate precursors (future floor-plate cells) in the dorsal non-involuting marginal zone.

Animals↗
PubMed2005

Histone deacetylase 1 regulates retinal neurogenesis in zebrafish by suppressing Wnt and Notch signaling pathways.

In the developing vertebrate retina, progenitor cells initially proliferate but begin to produce postmitotic neurons when neuronal differentiation occurs. However, the mechanism that determines whether retinal progenitor cells continue to proliferate or exit from the cell cycle and differentiate is largely unknown. Here, we report that histone deacetylase 1 (Hdac1) is required for the switch from proliferation to differentiation in the zebrafish retina. We isolated a zebrafish mutant, ascending and descending (add), in which retinal cells fail to differentiate into neurons and glial cells but instead continue to proliferate. The cloning of the add gene revealed that it encodes Hdac1. Furthermore, the ratio of the number of differentiating cells to that of proliferating cells increases in proportion to Hdac activity, suggesting that Hdac proteins regulate a crucial step of retinal neurogenesis in zebrafish. Canonical Wnt signaling promotes the proliferation of retinal cells in zebrafish, and Notch signaling inhibits neuronal differentiation through the activation of a neurogenic inhibitor, Hairy/Enhancer-of-split (Hes). We found that both the Wnt and Notch/Hes pathways are activated in the add mutant retina. The cell-cycle progression and the upregulation of Hes expression in the add mutant retina can be inhibited by the blockade of Wnt and Notch signaling, respectively. These data suggest that Hdac1 antagonizes these pathways to promote cell-cycle exit and the subsequent neurogenesis in zebrafish retina. Taken together, these data suggest that Hdac1 functions as a dual switch that suppresses both cell-cycle progression and inhibition of neurogenesis in the zebrafish retina.

Amino Acid Sequence↗
PubMed1993

Specifying the path of the intersegmental nerve of the Drosophila embryo: a role for Delta and Notch.

The intersegmental nerve (ISN) of the Drosophila embryo follows a reproducible course near the anterior border of each segment. Based on the experiments reported here, we suggest that growth of the axons constituting the nerve is guided, in part, by the transmembrane proteins Delta and Notch. In particular, we suggest that expression of Delta protein on a branch of the trachea provides a path for the nerve through the lateral part of the embryo, and that the growing axons use the Notch protein on their surfaces to recognize this path. Consistent with this idea, we show that disruption of the trachea abolishes the ability of the ISN to extend through this part of the embryonic periphery. Finally, we argue that the same regulatory network that directs these peripheral axons also specifies the trajectory of part of the axonal scaffold of the central nervous system.

Animals↗
PubMed1997

A family of mammalian Fringe genes implicated in boundary determination and the Notch pathway.

The formation of boundaries between groups of cells is a universal feature of metazoan development. Drosophila fringe modulates the activation of the Notch signal transduction pathway at the dorsal-ventral boundary of the wing imaginal disc. Three mammalian fringe-related family members have been cloned and characterized: Manic, Radical and Lunatic Fringe. Expression studies in mouse embryos support a conserved role for mammalian Fringe family members in participation in the Notch signaling pathway leading to boundary determination during segmentation. In mammalian cells, Drosophila fringe and the mouse Fringe proteins are subject to posttranslational regulation at the levels of differential secretion and proteolytic processing. When misexpressed in the developing Drosophila wing imaginal disc the mouse Fringe genes exhibit conserved and differential effects on boundary determination.

Amino Acid Sequence↗
PubMed1997

The Drosophila neurogenic gene big brain, which encodes a membrane-associated protein, acts cell autonomously and can act synergistically with Notch and Delta.

In the developing nervous system of Drosophila, cells in each proneural cluster choose between neural and epidermal cell fates. The neurogenic genes mediate the cell-cell communication process whereby one cell adopts the neural cell fate and prevents other cells in the cluster from becoming neural. In the absence of neurogenic gene function, most, if not all of the cells become neural. big brain is a neurogenic gene that encodes a protein with sequence similarity to known channel proteins. It is unique among the neurogenic genes in that previous genetic studies have not revealed any interaction between big brain and the other neurogenic genes. Furthermore, the neural hypertrophy in big brain mutant embryos is less severe than that in embryos mutant for other neurogenic genes. In this paper, we show by antibody staining that bib is expressed in tissues that give rise to neural precursors and in other tissues that are affected by loss of neurogenic gene function. By immunoelectron microscopy, we found that bib is associated with the plasma membrane and concentrated in apical adherens junctions as well as in small cytoplasmic vesicles. Using mosaic analysis in the adult, we demonstrate that big brain activity is required autonomously in epidermal precursors to prevent neural development. Finally, we demonstrate that ectopically expressed big brain acts synergistically with ectopically expressed Delta and Notch, providing the first evidence that big brain may function by augmenting the activity of the Delta-Notch pathway. These results are consistent with bib acting as a channel protein in proneural cluster cells that adopt the epidermal cell fate, and serving a necessary function in the response of these cells to the lateral inhibition signal.

Amino Acid Sequence↗
PubMed2001

A requirement for Notch in the genesis of a subset of glial cells in the Drosophila embryonic central nervous system which arise through asymmetric divisions.

In the Drosophila central nervous system (CNS) glial cells are known to be generated from glioblasts, which produce exclusively glia or neuroglioblasts that bifurcate to produce both neuronal and glial sublineages. We show that the genesis of a subset of glial cells, the subperineurial glia (SPGs), involves a new mechanism and requires Notch. We demonstrate that the SPGs share direct sibling relationships with neurones and are the products of asymmetric divisions. This mechanism of specifying glial cell fates within the CNS is novel and provides further insight into regulatory interactions leading to glial cell fate determination. Furthermore, we show that Notch signalling positively regulates glial cells missing (gcm) expression in the context of SPG development.

Animals↗
PubMed2005

Notch signaling in hematopoietic stem cells.

The molecular basis of the hematopoietic stem cell (HSC) "niche" has gradually been elucidated. This new knowledge may help us understand how the self-renewal of HSCs is physiologically regulated and may give us clues for developing methods for ex vivo HSC expansion. The Notch pathway is an environmental signaling system that may play an important role in the HSC niche. In this review, we focus on the role of Notch signaling in the regulation of hematopoietic stem and progenitor cells in both embryo and adult hematopoiesis and clarify what is known regarding the self-renewal of HSCs.

Animals↗
PubMed2005

Multiple signatures of positive selection downstream of notch on the X chromosome in Drosophila melanogaster.

To identify genomic regions affected by the rapid fixation of beneficial mutations (selective sweeps), we performed a scan of microsatellite variability across the Notch locus region of Drosophila melanogaster. Nine microsatellites spanning 60 kb of the X chromosome were surveyed for variation in one African and three non-African populations of this species. The microsatellites identified an approximately 14-kb window for which we observed relatively low levels of variability and/or a skew in the frequency spectrum toward rare alleles, patterns predicted at regions linked to a selective sweep. DNA sequence polymorphism data were subsequently collected within this 14-kb region for three of the D. melanogaster populations. The sequence data strongly support the initial microsatellite findings; in the non-African populations there is evidence of a recent selective sweep downstream of the Notch locus near or within the open reading frames CG18508 and Fcp3C. In addition, we observe a significant McDonald-Kreitman test result suggesting too many amino acid fixations species wide, presumably due to positive selection, at the unannotated open reading frame CG18508. Thus, we observe within this small genomic region evidence for both recent (skew toward rare alleles in non-African populations) and recurring (amino acid evolution at CG18508) episodes of positive selection.

Animals↗
PubMed2004

Differential expression of notch signaling-related transcripts accompanies pro-thymocyte proliferation and phenotype transition induced by epidermal growth factor plus insulin in fetal thymus organ cultures.

Thymus regression upon stressing stimuli, such as infectious diseases, is followed by organ reconstitution, paralleling its development in ontogeny. A narrow window of thymus development was here studied, encompassing the pro-T lymphoid precursor expansion during specification stages, by the use of epidermal growth factor plus insulin (INS) in murine fetal thymus organ cultures. Aiming to disclose signaling pathways related to these stages, cultured thymus lobes had their RNA extracted, for the search of transcripts differentially expressed using RNAse protection assays and reverse transcriptase-polymerase chain reactions. We found no difference that could explain INS-driven thymocyte growth, in the pattern of transcripts for death/proliferation mediators, or for a series of growth factor receptors and transcriptional regulators known as essential for thymus development. Thymocyte suspensions from cultured lobes, stained for phenotype analysis by fluorescence activated cell sorting, showed a decreased staining for Notch1 protein at cell surfaces upon INS addition. We analyzed the expression of Notch-related elements, and observed the recruitment of a specific set of transcripts simultaneous and compatible with INS-driven thymocyte growth, namely, transcripts for Notch3, for its ligand Jagged2, and for Deltex1, a mediator of a poorly characterized alternative pathway downstream of the Notch receptor.

Animals↗
PubMed2004

Notch governing mature T cell differentiation.

The differentiation of naive T cells to effector/memory T cells is regulated by a variety of factors. The recent advance of the contribution of Notch signaling in this differentiation step has provided a new path to better understand the acquisition or persistence of effector function of mature T cells. In this review, we summarize emerging and, in some points, conflicting evidence for Notch signaling on mature T cell activation and differentiation.

Animals↗
PubMed2005

Propensity of adult lymphoid progenitors to progress to DN2/3 stage thymocytes with Notch receptor ligation.

Notch family receptors control critical events in the production and replenishment of specialized cells in the immune system. However, it is unclear whether Notch signaling regulates abrupt binary lineage choices in homogeneous progenitors or has more gradual influence over multiple aspects of the process. A recently developed coculture system with Delta 1-transduced stromal cells is being extensively used to address such fundamental questions. Different from fetal progenitors, multiple types of adult marrow cells expanded indefinitely in murine Delta-like 1-transduced OP9 cell cocultures, progressed to a DN2/DN3 thymocyte stage, and slowly produced TCR(+) and NK cells. Long-term cultured cells of this kind retained some potential for T lymphopoiesis in vivo. Adult marrow progressed through double-positive and single-positive stages only when IL-7 concentrations were low and passages were infrequent. Lin(-)c-Kit(low)GFP(+)IL-7Ralpha(+/-) prolymphocytes were the most efficient of adult bone marrow cells in short-term cultures, but the assay does not necessarily reflect cells normally responsible for replenishing the adult thymus. Although marrow-derived progenitors with Ig D(H)-J(H) rearrangements acquired T lineage characteristics in this model, that was not the case for more B committed cells with V(H)-D(H)J(H) rearrangement products.

Aging↗