http://www.dspace.cam.ac.uk:80/handle/1810/239043 Sun, 26 May 2013 03:30:45 GMT 2013-05-26T03:30:45Z http://www.dspace.cam.ac.uk:80/handle/1810/241728 Title: Chondroitin sulfates in the developing rat hindbrain confine commissural projections of vestibular nuclear neurons Authors: Kwok, Jessica CF; Yuen, Ying Lai; Lau, Wai Kit; Zhang, Fu Xing; Fawcett, James W; Chan, Ying Shing; Shum, Daisy KY Abstract: Abstract Background Establishing correct neuronal circuitry is crucial to proper function of the vertebrate nervous system. The abundance of chondroitin sulfate (CS) proteoglycans in embryonic neural environments suggests that matrix proteoglycans regulate axonal projections when fiber tracts have not yet formed. Among the early-born neurons, the vestibular nucleus (VN) neurons initiate commissural projections soon after generation at E12.5 and reach the contralateral target by E15.5 in the rat hindbrain. We therefore exploited 24-hour cultures (1 day in vitro (DIV)) of the rat embryos and chondroitinase ABC treatment of the hindbrain matrix to reveal the role of CS moieties in axonal initiation and projection in the early hindbrain. Results DiI tracing from the VN at E12.5(+1 DIV) showed contralaterally projecting fibers assuming fascicles that hardly reached the midline in the controls. In the enzyme-treated embryos, the majority of fibers were unfasciculated as they crossed the midline at 90°. At E13.5(+1 DIV), the commissural projections formed fascicles and crossed the midline in the controls. Enzyme treatment apparently did not affect the pioneer axons that had advanced as thick fascicles normal to the midline and beyond, towards the contralateral VN. Later projections, however, traversed the enzyme-treated matrix as unfasciculated fibers, deviated from the normal course crossing the midline at various angles and extending beyond the contralateral VN. This suggests that CSs also limit the course of the later projections, which otherwise would be attracted to alternative targets. Conclusions CS moieties in the early hindbrain therefore control the course and fasciculation of axonal projections and the timing of axonal arrival at the target. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Fri, 03 Feb 2012 00:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/241728 2012-02-03T00:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238816 Title: A Wnt1 Regulated Frizzled-1/beta-Catenin Signaling Pathway as a Candidate Regulatory Circuit Controlling Mesencephalic Dopaminergic Neuron-Astrocyte Crosstalk : Therapeutical Relevance for Neuron Survival and Neuroprotection Authors: L'Episcopo, Francesca; Serapide, Maria F; Tirolo, Cataldo; Testa, Nunzio; Caniglia, Salvatore; Morale, Maria C; Pluchino, Stefano; Marchetti, Bianca Abstract: Abstract Background Dopamine-synthesizing (dopaminergic, DA) neurons in the ventral midbrain (VM) constitute a pivotal neuronal population controlling motor behaviors, cognitive and affective brain functions, which generation critically relies on the activation of Wingless-type MMTV integration site (Wnt)/β-catenin pathway in their progenitors. In Parkinson's disease, DA cell bodies within the substantia nigra pars compacta (SNpc) progressively degenerate, with causes and mechanisms poorly understood. Emerging evidence suggests that Wnt signaling via Frizzled (Fzd) receptors may play a role in different degenerative states, but little is known about Wnt signaling in the adult midbrain. Using in vitro and in vivo model systems of DA degeneration, along with functional studies in both intact and SN lesioned mice, we herein highlight an intrinsic Wnt1/Fzd-1/β-catenin tone critically contributing to the survival and protection of adult midbrain DA neurons. Results In vitro experiments identifie Fzd-1 receptor expression at a mRNA and protein levels in dopamine transporter (DAT) expressing neurons, and demonstrate the ability of exogenous Wnt1 to exert robust neuroprotective effects against Caspase-3 activation, the loss of tyrosine hydroxylase-positive (TH+) neurons and [3H] dopamine uptake induced by different DA-specific insults, including serum and growth factor deprivation, 6-hydroxydopamine and MPTP/MPP+. Co-culture of DA neurons with midbrain astrocytes phenocopies Wnt1 neuroprotective effects, whereas RNA interference-mediated knockdown of Wnt1 in midbrain astrocytes markedly reduces astrocyte-induced TH+ neuroprotection. Likewise, silencing β-catenin mRNA or knocking down Fzd-1 receptor expression in mesencephalic neurons counteract astrocyte-induced TH+ neuroprotection. In vivo experiments document Fzd-1 co-localization with TH+ neurons within the intact SNpc and blockade of Fzd/β-catenin signaling by unilateral infusion of a Fzd/β-catenin antagonist within the SN induces reactive astrocytosis and acutely inhibits TH+ neuron survival in ipsilateral SNpc, an effect efficiently prevented by pharmacological activation of β-catenin signaling within the SNpc. Conclusion These results defining a novel Wnt1/Fzd-1/β-catenin astrocyte-DA autoprotective loop provide a new mechanistic inside into the regulation of pro-survival processes, with potentially relevant consequences for drug design or drug action in Parkinson's disease. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Tue, 12 Jul 2011 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238816 2011-07-12T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238278 Title: P53 autoantibodies in 1006 patients followed up for breast cancer Authors: Metcalfe, Su; Wheeler, Terence K; Picken, Sheila; Negus, Susanne; Milner, A Jo Abstract: Statement of findings Serial plasma samples from 1006 patients with breast cancer revealed: (i) no correlation of p53 autoantibody status with disease status at the time of sample collection, or with menopausal status at time of primary diagnosis of breast cancer; (ii) 155 out of 1006 (15%) of patients were positive for p53 autoantibodies, and these patients tended to have a persistent autoantibody status throughout follow up, irrespective of disease behaviour; and (iii) where a negative autoantibody status was found at primary diagnosis of breast cancer, this negative status persisted throughout follow up, irrespective of later disease behaviour. We conclude that screening for p53 autoantibody status is not informative on residual tumour activity nor on therapeutic responsiveness. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Sun, 20 Aug 2000 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238278 2000-08-20T23:00:00Z http://www.dspace.cam.ac.uk:80/handle/1810/238192 Title: Bridging spinal cord injuries Abstract: Abstract One strategy for spinal cord injury repair is to make cellular bridges that support axon regeneration. However, the bridging cells often fail to integrate with host tissue and may lead to increased pain sensitivity. Recent work has tested bridging with two forms of progenitor-derived astrocyte. One type integrates, suppresses scar formation and promotes axon regeneration, whereas another very similar type, reported in Journal of Biology, does not support regeneration and increases pain sensitivity. Description: RIGHTS : This article is licensed under the BioMed Central licence at http://www.biomedcentral.com/about/license which is similar to the 'Creative Commons Attribution Licence'. In brief you may : copy, distribute, and display the work; make derivative works; or make commercial use of the work - under the following conditions: the original author must be given credit; for any reuse or distribution, it must be made clear to others what the license terms of this work are. Tue, 14 Oct 2008 23:00:00 GMT http://www.dspace.cam.ac.uk:80/handle/1810/238192 2008-10-14T23:00:00Z