UK National Institute for Medical Research

Plympton, United Kingdom

UK National Institute for Medical Research

Plympton, United Kingdom
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Urban N.,UK National Institute for Medical Research | Guillemot F.,UK National Institute for Medical Research
Frontiers in Cellular Neuroscience | Year: 2014

Neurogenesis persists in adult mammals in specific brain areas, known as neurogenic niches. Adult neurogenesis is highly dynamic and is modulated by multiple physiological stimuli and pathological states. There is a strong interest in understanding how this process is regulated, particularly since active neuronal production has been demonstrated in both the hippocampus and the subventricular zone (SVZ) of adult humans. The molecular mechanisms that control neurogenesis have been extensively studied during embryonic development. Therefore, we have a broad knowledge of the intrinsic factors and extracellular signaling pathways driving proliferation and differentiation of embryonic neural precursors. Many of these factors also play important roles during adult neurogenesis, but essential differences exist in the biological responses of neural precursors in the embryonic and adult contexts. Because adult neural stem cells (NSCs) are normally found in a quiescent state, regulatory pathways can affect adult neurogenesis in ways that have no clear counterpart during embryogenesis. BMP signaling, for instance, regulates NSC behavior both during embryonic and adult neurogenesis. However, this pathway maintains stem cell proliferation in the embryo, while it promotes quiescence to prevent stem cell exhaustion in the adult brain. In this review, we will compare and contrast the functions of transcription factors (TFs) and other regulatory molecules in the embryonic brain and in adult neurogenic regions of the adult brain in the mouse, with a special focus on the hippocampal niche and on the regulation of the balance between quiescence and activation of adult NSCs in this region. © 2014 Urbán and Guillemot.

Birdsall N.J.M.,UK National Institute for Medical Research
Trends in Pharmacological Sciences | Year: 2010

There is a large body of experimental evidence that is compatible with the presence of heterodimers of the major A subclass of G protein-coupled receptors (GPCRs) and suggests that these heterodimers might have different functional properties from those of the monomers (or homodimers) of the individual receptors that engage in heterodimer formation. The question is whether there are allosteric interactions across the receptor-receptor interface of a heterodimer that modulate the binding properties of the heterodimer components and thereby change their pharmacology. In this review, I examine published experimental evidence from radioligand binding studies in the context of different models of allosterism and discuss a number of apparently discrepant results. The analysis suggests that more experimental data are required if equal, two-way, crossreceptor interactions within a GPCR heterodimer, at the level of binding, are to be unequivocally demonstrated. © 2010 Elsevier Ltd.

Hulme E.C.,UK National Institute for Medical Research
Trends in Pharmacological Sciences | Year: 2013

The crystal structures of antagonist and agonist complexes of isolated β2 and β1 adrenoceptors have recently been supplemented by antagonist structures of M2 and M3 muscarinic acetylcholine receptors. Importantly, a structure of an agonist-ligated β2 adrenoceptor complexed with its cognate G protein has provided the first view of a ternary complex representing the transition state in agonist-mediated G protein activation. This review interprets these G-protein-coupled receptor (GPCR) structures through the focus provided by extensive mutagenesis studies on muscarinic receptors, revealing an activation mechanism that is both modular and dynamic. Specific motifs, based around highly conserved residues, functionalise the seven-transmembrane architecture of these receptors. While exploiting conserved motifs, the ligand binding and signal transduction pathways work around and through water-containing cavities, an emerging feature of GPCR structures. These cavities may have undergone evolutionary selection to adapt GPCRs to particular signalling niches, and may provide targeting opportunities to enhance drug selectivity. © 2012 Elsevier Ltd All rights reserved.

Alexandre C.,UK National Institute for Medical Research | Baena-Lopez A.,UK National Institute for Medical Research | Vincent J.-P.,UK National Institute for Medical Research
Nature | Year: 2014

Wnts are evolutionarily conserved secreted signalling proteins that, in various developmental contexts, spread from their site of synthesis to form a gradient and activate target-gene expression at a distance. However, the requirement for Wnts to spread has never been directly tested. Here we used genome engineering to replace the endogenous wingless gene, which encodes the main Drosophila Wnt, with one that expresses a membrane-tethered form of the protein. Surprisingly, the resulting flies were viable and produced normally patterned appendages of nearly the right size, albeit with a delay. We show that, in the prospective wing, prolonged wingless transcription followed by memory of earlier signalling allows persistent expression of relevant target genes. We suggest therefore that the spread of Wingless is dispensable for patterning and growth even though it probably contributes to increasing cell proliferation. © 2014 Macmillan Publishers Limited.

Rizzoti K.,UK National Institute for Medical Research
European Journal of Neuroscience | Year: 2010

Stem cells/progenitors are being discovered in a growing number of adult tissues. They have been hypothesized for a long time to exist in the pituitary, especially because this gland is characterized by its plasticity as it constantly adapts its hormonal response to evolving needs, under the control of the hypothalamus. Recently, five labs have reported the presence of adult progenitors in the gland and shown their endocrine differentiation potential, using different in vitro assays, selection methods and markers to purify and characterize these similar cell populations. These will be discussed here, highlighting common points, and also differences. Thanks to these recent developments it is now possible to integrate progenitors into the physiology of the gland, and uncover their participation in normal but also pathological situations. Moreover, experimental situations inducing generation of new endocrine cells can now be re-visited in light of the involvement of progenitors, and also used to better understand their role. Some of these aspects will also be developed in this review. © 2010 Medical Research Council. European Journal of Neuroscience © 2010 Federation of European Neuroscience Societies and Blackwell Publishing Ltd.

Guillemot F.,UK National Institute for Medical Research | Zimmer C.,Institut Universitaire de France
Neuron | Year: 2011

The generation of a functional nervous system involves a multitude of steps that are controlled by just a few families of extracellular signaling molecules. Among these, the fibroblast growth factor (FGF) family is particularly prominent for the remarkable diversity of its functions. FGFs are best known for their roles in the early steps of patterning of the neural primordium and proliferation of neural progenitors. However, other equally important functions have emerged more recently, including in the later steps of neuronal migration, axon navigation, and synaptogenesis. We review here these diverse functions and discuss the mechanisms that account for this unusual range of activities. FGFs are essential components of most protocols devised to generate therapeutically important neuronal populations in vitro or to stimulate neuronal repair in vivo. How FGFs promote the development of the nervous system and maintain its integrity will thus remain an important focus of research in the future. © 2011 Elsevier Inc.

Spence P.J.,UK National Institute for Medical Research
Nature protocols | Year: 2011

The rodent malaria parasite Plasmodium chabaudi chabaudi shares many features with human malaria species, including P. falciparum, and is the in vivo model of choice for many aspects of malaria research in the mammalian host, from sequestration of parasitized erythrocytes, to antigenic variation and host immunity and immunopathology. This protocol describes an optimized method for the transformation of mature blood-stage P.c. chabaudi and a description of a vector that targets efficient, single crossover integration into the P.c. chabaudi genome. Transformed lines are reproducibly generated and selected within 14-20 d, and show stable long-term protein expression even in the absence of drug selection. This protocol, therefore, provides the scientific community with a robust and reproducible method to generate transformed P.c. chabaudi parasites expressing fluorescent, bioluminescent and model antigens that can be used in vivo to dissect many of the fundamental principles of malaria infection.

Briscoe J.,UK National Institute for Medical Research
Nature reviews. Molecular cell biology | Year: 2013

The cloning of the founding member of the Hedgehog (HH) family of secreted proteins two decades ago inaugurated a field that has diversified to encompass embryonic development, stem cell biology and tissue homeostasis. Interest in HH signalling increased when the pathway was implicated in several cancers and congenital syndromes. The mechanism of HH signalling is complex and remains incompletely understood. Nevertheless, studies have revealed novel biological insights into this system, including the function of HH lipidation in the secretion and transport of this ligand and details of the signal transduction pathway, which involves Patched 1, Smoothened and GLI proteins (Cubitus interruptus in Drosophila melanogaster), as well as, in vertebrates, primary cilia.

Berry M.P.,UK National Institute for Medical Research
Current opinion in immunology | Year: 2013

Tuberculosis (TB) remains a disease of considerable mortality and morbidity. Studies employing microarrays to derive transcriptional profiles of the host response during TB, which combined with data from experimental systems have highlighted a potentially detrimental role for type I interferons during infection, with important implications for vaccine and therapeutic development. In addition, these studies have provided candidate biomarkers which may advance diagnosis and treatment monitoring. These studies thus exemplify the promise of a systems biology approach to study complex infectious disease such as TB. Copyright © 2013 Elsevier Ltd. All rights reserved.

Prischi F.,UK National Institute for Medical Research
Nature communications | Year: 2010

Reduced levels of frataxin, an essential protein of as yet unknown function, are responsible for causing the neurodegenerative pathology Friedreich's ataxia. Independent reports have linked frataxin to iron-sulphur cluster assembly through interactions with the two central components of this machinery: desulphurase Nfs1/IscS and the scaffold protein Isu/IscU. In this study, we use a combination of biophysical methods to define the structural bases of the interaction of CyaY (the bacterial orthologue of frataxin) with the IscS/IscU complex. We show that CyaY binds IscS as a monomer in a pocket between the active site and the IscS dimer interface. Recognition does not require iron and occurs through electrostatic interactions of complementary charged residues. Mutations at the complex interface affect the rates of enzymatic cluster formation. CyaY binding strengthens the affinity of the IscS/IscU complex. Our data suggest a new paradigm for understanding the role of frataxin as a regulator of IscS functions.

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