Ethics in aesthetics.
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Esthetics, Dental↗
Biomedical subjects
S Bray
Publications and source records attributed to S Bray.
Notch pathway: making sense of suppressor of hairless.
Suppressor of Hairless (Su(H)) is a DNA-binding protein component of the Notch signalling pathway, thought to be required, with a fragment of the Notch receptor, for target gene activation. Recent studies show that this is only one side of the story: target gene enhancers may be regulated by Su(H) in a variety of different ways.
Animals↗
A model Notch response element detects Suppressor of Hairless-dependent molecular switch.
Cell-cell signaling mediated by Notch is critical during many different developmental processes for the specification or restriction of cell fates. Currently, the only known transduction pathway involves a DNA binding protein, Suppressor of Hairless [Su(H)] in Drosophila and CBF1 in mammals, and results in the direct activation of target genes. It has been proposed that in the absence of Notch, Su(H)/CBF1 acts as a repressor and is converted into an activator through interactions with the Notch intracellular domain [1--4]. Recently, we have also suggested that the activation of specific target genes requires synergy between Su(H) and other transcriptional activators [5]. Here we have designed an assay that allows us to directly test these hypotheses in vivo. Our results clearly demonstrate that Su(H) is able to function as the core of a molecular switch, repressing transcription in the absence of Notch and activating in the presence of Notch. In its capacity as an activator, Su(H) can cooperate synergistically with a DNA-bound transcription factor, Grainyhead. These interactions indicate a simple model for Notch target-gene regulation that could explain the precision of gene activation elicited by Notch signaling in different developmental fate decisions.
Animals↗
Scalar timing without reference memory? Episodic temporal generalization and bisection in humans.
Three experiments tested whether the scalar property of timing could occur when humans timed short durations under conditions in which it was unlikely that they developed reference memories of temporal "standards". Experiment 1 used an episodic version of a temporal generalization task where judgements were made of the potential equality of two durations presented on each trial. Unknown to the subject, one of these was always 200, 400, 600, or 800 ms, and the other was of variable duration. Temporal generalization gradients showed the scalar property of superimposition at standard values greater than 200 ms. Experiment 2 used a variant of the "roving bisection" method invented by Rodriguez-Girones and Kacelnik (1998) modified so that the scalar property of timing could be observed empirically. Data from bisection with short/long standard pairs of 100/400, 200/800, and 300/1,200 ms showed nearly perfect scalar-type superimposition. Experiment 3 again used episodic temporal generalization, but durations were never repeated and came from three distinct time ranges. Superimposition was found across these ranges except for the shortest visual stimuli timed. The data suggested that scalar timing could occur in humans in conditions where the formation of reference memories of temporal standards was highly improbable.
Generalization, Psychological↗
New monoclonal antibodies recognizing the p53 tumour suppressor protein homologue p73.
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Animals↗
Dissecting the mechanisms of suppressor of hairless function.
Suppressor of Hairless [Su(H)] is a DNA-binding protein that is the main intracellular transducer of the Notch signaling pathway in Drosophila. Several different mechanisms have been proposed to account for the activation of Su(H) by Notch. To further investigate how Su(H) activity is regulated we have used misexpression assays with wild-type Su(H) and with modified forms of Su(H) that contained a nuclear localization signal [Su(H)NLS], a transcriptional activation domain [Su(H)VP16], or a deletion of the domain required for interaction with the antagonist Hairless [Su(H)DeltaH]. Only Su(H)VP16 was able to mimic Notch activation effectively in the Drosophila wing, in agreement with the model that Notch activity normally confers coactivator function on Su(H). Neither nuclear localization nor elimination of Hairless binding was sufficient for activation. The phenotypes produced by overexpression of Su(H)wt and Su(H)NLS indicated a mixture of both increased and reduced Notch pathway activity and point to a role for Su(H) in both activation and repression of gene expression, as has been proposed for the mammalian homologue CBF1. Some phenotypes were equivalent to Notch loss-of-function, with wing-nicks and inhibition of a subset of target genes, which is most consistent with the ectopic proteins displacing a Su(H)-coactivator complex. Conversely, other phenotypes were equivalent to Notch gain-of-function, with wing-overgrowths and ectopic target-gene expression. These effects can be explained by the ectopic Su(H)/Su(H)NLS titrating a repressor complex. The wing-overgrowth phenotype is sensitive to the dose of Hairless and the phenotypes produced by coexpressing Su(H) and Hairless suggest that Hairless could form a component of this repressive complex.
Animals↗
Developmental biology. Post-expressionist flies.
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Animals↗
Spatially restricted factors cooperate with notch in the regulation of Enhancer of split genes.
Expression of the Drosophila Enhancer of split [E(spl)] genes, and their homologues in other species, is dependent on Notch activation. The seven E(spl) genes are clustered in a single complex and their functions overlap significantly; however, the individual genes have distinct patterns of expression. To investigate how this regulation is achieved and to find out whether there is shared or cross regulation between E(spl) genes, we have analysed the enhancer activity of sequences from the adjacent E(spl)mbeta, E(spl)mgamma and E(spl)mdelta genes and made comparisons to E(spl)m8. We find that although regulatory elements can be shared, most aspects of the expression of each individual gene are recapitulated by small (400-500 bp) evolutionarily conserved enhancers. Activated Notch or a Suppressor of Hairless-VP16 fusion are only sufficient to elicit transcription from the E(spl) enhancers in a subset of locations, indicating a requirement for other factors. In tissue culture cells, proneural proteins synergise with Suppressor of Hairless and Notch to promote expression from E(spl)mgamma and E(spl)m8, but this synergy is only observed in vivo with E(spl)m8. We conclude that additional factors besides the proneural proteins limit the response of E(spl)mgamma in vivo. In contrast to the other genes, E(spl)mbeta exhibits little response to proneural proteins and its high level of activity in the wing imaginal disc suggests that wing-specific factors cooperate with Notch to activate the E(spl)mbeta enhancer. These results demonstrate that Notch activity must be integrated with other transcriptional regulators and, since the activation of target genes is critical in determining the developmental consequences of Notch activity, provide a framework for understanding Notch function in different developmental contexts.
Animals↗
Pattern formation: Wingless on the move.
Wingless is a key morphogen in Drosophila. Although it is evident that Wingless acts at a distance from its site of synthesis, there is considerable debate about how the protein travels across a field of cells. Recent studies have provided important new insights into this process, though the issue is still far from being resolved.
Animals↗
Planar polarity: out of joint?
Epithelial structures, such as the wing hairs and ommatidia in Drosophila, are aligned in the plane of the epithelium. This planar polarity requires the transmembrane receptor Frizzled. Recent studies have shed new light on mechanisms that could be involved in generating or transducing the polarity signal.
Animals↗
Specificity and promiscuity among proneural proteins.
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Animals↗
Time- and dose-related changes in the thickness of skin in the pig after irradiation with single doses of thulium-170 beta particles.
Time-related changes in skin thickness have been evaluated in the pig using a noninvasive ultrasound technique after exposure to a range of single doses of 0.97 MeV beta particles from (170)Tm plaques. The reduction in relative skin thickness developed in two phases; the separation into two phases was statistically justified only after 120 Gy (P = 0.04). The first phase was between 12 weeks and 24 weeks after irradiation. No further changes were seen until 48-60 weeks after irradiation, when a second phase of skin thinning was observed. No further changes in relative skin thickness were seen in the follow-up period of 104 weeks. The timing of these phases of relative skin thinning was totally independent of the radiation dose; however, the severity of each phase of radiation-induced skin thinning was related to the dose. The pattern of changes was similar to that reported previously after irradiation with 2.27 MeV beta particles from (90)Sr/(90)Y, but the degree of dermal thinning was less for a similar skin surface dose. From a comparison of the depth-dose distribution of the beta particles from the two radionuclides, it was concluded that the target cell population responsible for both the first and second phase of skin thinning in pig skin after irradiation may be located at approximately 800 microm depth. This corresponds to an area in the reticular dermis in pig skin and may be the appropriate site at which to measure the average dose to the dermal tissue.
Animals↗
Drosophila development: Scalloped and Vestigial take wing.
The proteins Scalloped and Vestigial are known from genetic studies to play a part in Drosophila wing development. Recent results show how they interact with each other, and in combination with other transcription factors, to confer specific patterns of expression within the wing.
Animals↗
Distinct expression patterns of different enhancer of split bHLH genes during embryogenesis of Drosophila melanogaster.
E(spl) bHLH genes are targets of the Notch pathway: they are transcriptionally activated in response to the Notch signal. Yet, during imaginal development, additional regulatory factors appear to modulate transcription resulting in different expression patterns. During early embryogenesis all E(spl) bHLH genes are expressed in roughly the same domain, namely the neurogenic ectoderm. Within this region these seven genes show a highly dynamic, yet distinct transcriptional activity. Our analysis further detected tissue specific expression of some E(spl) genes at later embryonic stages. Prominent differences were observed in the dorsolateral and procephalic neuroectodermal regions as well as in the mesoderm. These observations indicate that other factors in addition to the Notch signal participate in the regulation of the individual E(spl) genes not only in imaginal tissues but also during neuroblast specification and other cell fate determination events in the embryo.
Animals↗