Biomedical subjects

Sarah J Bray

Publications and source records attributed to Sarah J Bray.

5 recordsLinked to original sources

PubMed2006

Notch signalling: a simple pathway becomes complex.

A small number of signalling pathways are used iteratively to regulate cell fates, cell proliferation and cell death in development. Notch is the receptor in one such pathway, and is unusual in that most of its ligands are also transmembrane proteins; therefore signalling is restricted to neighbouring cells. Although the intracellular transduction of the Notch signal is remarkably simple, with no secondary messengers, this pathway functions in an enormous diversity of developmental processes and its dysfunction is implicated in many cancers.

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PubMed2005

Regulation of post-embryonic neuroblasts by Drosophila Grainyhead.

The Drosophila post-embryonic neuroblasts (pNBs) are neural stem cells that persist in the larval nervous system where they proliferate to produce neurons for the adult CNS. These pNBs provide a good model to investigate mechanisms regulating the maintenance and proliferation of stem cells. The transcription factor Grainyhead (Grh), which is required for morphogenesis of epidermal and tracheal cells, is also expressed in all pNBs. Here, we show that grh is essential for pNBs to adopt the stem cell programme appropriate to their position within the CNS. In grh mutants the abdominal pNBs produced more progeny while the thoracic pNBs, in contrast, divided less and produced fewer progeny than wild type. We investigated three candidates; the Neuroblast identify gene Castor, the signalling molecule Notch and the adhesion protein E-Cadherin, to determine whether they could mediate these effects. Neither Castor nor Notch fulfilled the criteria for intermediaries, and in particular Notch activity was found to be dispensable for the normal proliferation and survival of the pNBs. In contrast E-Cadherin, which has been shown to regulate pNB proliferation, was present at greatly reduced levels in the grh mutant pNBs. Furthermore, ectopic expression of Grh was sufficient to promote ectopic E-Cadherin and two conserved Grh-binding sites were identified in the E-Cadherin/shotgun flanking sequences, arguing that this gene is a downstream target. Thus one way Grh could regulate pNBs is through expression of E-cadherin, a protein that is thought to mediate interactions with the glial niche.

Animals↗

PubMed2005

The Drumstick/Lines/Bowl regulatory pathway links antagonistic Hedgehog and Wingless signaling inputs to epidermal cell differentiation.

Hedgehog and Wingless signaling in the Drosophila embryonic epidermis represents one paradigm for organizer function. In patterning this epidermis, Hedgehog and Wingless act asymmetrically, and consequently otherwise equivalent cells on either side of the organizer follow distinct developmental fates. To better understand the downstream mechanisms involved, we have investigated mutations that disrupt dorsal epidermal pattern. We have previously demonstrated that the gene lines contributes to this process. Here we show that the Lines protein interacts functionally with the zinc-finger proteins Drumstick (Drm) and Bowl. Competitive protein-protein interactions between Lines and Bowl and between Drm and Lines regulate the steady-state accumulation of Bowl, the downstream effector of this pathway. Lines binds directly to Bowl and decreases Bowl abundance. Conversely, Drm allows Bowl accumulation in drm-expressing cells by inhibiting Lines. This is accomplished both by outcompeting Bowl in binding to Lines and by redistributing Lines to the cytoplasm, thereby segregating Lines away from nuclearly localized Bowl. Hedgehog and Wingless affect these functional interactions by regulating drm expression. Hedgehog promotes Bowl protein accumulation by promoting drm expression, while Wingless inhibits Bowl accumulation by repressing drm expression anterior to the source of Hedgehog production. Thus, Drm, Lines, and Bowl are components of a molecular regulatory pathway that links antagonistic and asymmetric Hedgehog and Wingless signaling inputs to epidermal cell differentiation. Finally, we show that Drm and Lines also regulate Bowl accumulation and consequent patterning in the epithelia of the foregut, hindgut, and imaginal discs. Thus, in all these developmental contexts, including the embryonic epidermis, the novel molecular regulatory pathway defined here is deployed in order to elaborate pattern across a field of cells.

Animals↗

PubMed2005

Black-white disparities in HIV/AIDS: the role of drug policy and the corrections system.

African Americans in the United States are disproportionately affected by HIV/AIDS. We focus in this paper on the structural and contextual sources of HIV/AIDS risk, and suggest that among the most important of these sources are drug policy and the corrections system. In particular, high rates of exposure to the corrections system (including incarceration, probation, and parole) spurred in large part by federal and state governments' self-styled war on drugs in the United States, have disproportionately affected African Americans. We review a wide range of research literature to suggest how exposure to the corrections system may affect the HIV/AIDS related risks of drug users in general, and the disproportionate HIV risk faced by African Americans in particular. We then discuss the implications of the information reviewed for structural interventions to address African American HIV-related risk. Future research must further our understanding of the relations among drug policy, corrections, and race-based disparities in HIV/AIDS.

Black or African American↗

PubMed2003

Bowl is required downstream of Notch for elaboration of distal limb patterning.

In the Drosophila leg, activation of Notch leads to the establishment of the joints that subdivide the appendage into segments. We find that mutations in bowl result in similar phenotypes to Notch, causing fusion and truncations of tarsal segments (tarsomeres) and, like its close relative Odd-skipped, Bowl is produced in response to Notch signalling at a subset of segment boundaries. However, despite the fact that bowl mutant clones result in fusion of tarsomeres, Bowl protein is only found at the t1/tibial and t5/pretarsal boundaries, not at tarsomere joints. One hypothesis to reconcile these data is that bowl has a role at an earlier stage in tarsal development. We therefore investigated the effects of bowl mutations on the expression of leg 'gap' genes that confer regional identity on the developing leg. Several of these genes have altered expression in bowl mutant cells. For example, bric-a-brac2 is normally expressed in the central part of the tarsus domain but expands into distal and proximal regions in bowl clones. Conversely, ectopic bowl leads to a reduction in bric-a-brac2, with a concomitant expansion of proximal (t1) and distal (t5) tarsomere fates. The bowl gene is therefore required for the elaboration of pattern in the tarsus and its effects suggest a progressive model for the determination of P/D identities. This mechanism might be important in the diversification of arthropod limbs, because it explains how segmented tarsomeres could have arisen from an ancestral limb with an unsegmented tarsus.

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