|
|||||
|
The NUS/UCL/KI Neuroscience Workshop 2016 is a 2-day symposium and workshop organised by NUS during 25-26 January featuring neuroscientists from two major NUS partner universities, University College London and Karolinska Institute in Stockholm, as well as local speakers from NUS, Duke-NUS, A*STAR, NNI and NTU. For more information and registration please visit the Workshop website. Our latest paper describes new NMR structures of the death domain in complex with downstream interactions RhoGDI and RIP2 as well as the death domain dimer. These are the first structural insights into p75NTR signaling and reveal many surprises for the death domain superfamily. The paper is now available online at eLife. Death domains (DDs) mediate assembly of oligomeric complexes for activation of downstream signaling pathways through incompletely understood mechanisms. We report structures of complexes formed by the DD of p75 neurotrophin receptor (p75NTR) with RhoGDI, for activation of the RhoA pathway, with caspase recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway, and with itself, revealing how DD dimerization controls access of intracellular effectors to the receptor. RIP2 CARD and RhoGDI bind to p75NTR DD at partially overlapping epitopes with over 100-fold difference in affinity, revealing the mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The p75NTR DD forms non-covalent, low-affinity symmetric dimers in solution. The dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting a model of receptor activation triggered by separation of DDs. These structures reveal how competitive protein-protein interactions orchestrate the hierarchical activation of downstream pathways in non-catalytic receptors. Senior RF Lin Zhi, NMR wizard and first lab member to be hired at our NUS lab, moves on to initiate his independent career after successful postdoc period at the lab. Lin Zhi will be group leader at Tianjin University in China. He remains a Visiting Research Fellow of our Department and we look forward to continued collaborations with him. All the best for you Lin Zhi! Eunice Sim holds a Bachelor in Science from the University of Western Australia. Until recently, she worked as Senior Laboratory Officer at the Advanced Molecular Pathology Laboratory of the Institute of Molecular & Cell Biology, A*STAR, Singapore. Eunice joins the NUS group to assist with various technical tasks, including mouse genotyping and histological analyses. Ee-Soo Lee obtained a PhD from the University of Groningen, The Netherlands, under the direction of Prof. Martin Harmsen. Her doctoral studies were based on investigations of the interplay between TGF-β and fluid shear stress in regulation of endothelial cell phenotype and functions, in the context of oxidative stress and cellular senescence. Ee-Soo is joining our nascent metabolism team to focus on studies at at understanding the signaling mechanisms by which teh action receptor ALK7 regulates catecholamine sensitivity in adipocytes. Chang Liu defended her thesis at the University of Sydney, Australia, under the direction of Prof. Jürgen Götz. Her doctoral studies were aimed towards addressing the distribution and physiological function of tau isoforms using tau isoform-specific monoclonal antibodies. Liu is joining our NUS group to lead a new line of research aimed towards the elucidation of the roles of neurotrophin signaling in cerebrovascular disease, focusing on their actions on cellular elements of the brain microvasculature under normal conditions and following cerebrovascular damage and AD-related neurodegeneration. A Research Assistant/Associate is currently being recruited to our laboratory in the Centre for Life Sciences, NUS campus. The successful candidate will be a dynamic, service-minded person, with a solid research background in molecular biology, tissue culture, histological techniques and/or mouse genetics methods. He/she will have a strong presence in the laboratory by assisting the group by with experimental lab routines, including maintenance of mouse colonies, genotyping, molecular biology and cell culture experiments, as well as conducting research together with other lab members or independently.
Work at the laboratory focuses on understanding the functions and signaling mechanisms of neuronal growth factors and their receptors in neural development, injury responses and metabolic regulation, for the development of better therapies to diseases of the nervous system and metabolism. Applications including CV and names plus email addresses of three referees should be sent by email before August 20 to Prof. Carlos Ibanez UPDATE (09/2015): this position has been filled. Raj Kamal Srivastava obtained his PhD in 2008 at the Department of Zoology, Faculty of Science in Banaras Hindu University, Varanasi, India. He did postdoctoral studies at the Institute for Physiological Chemistry and Pathobiochemistry, Johannes Gutenberg University of Mainz, Germany. His studied the role of central and peripheral CB1 receptor in obesity and behavioral disorder using transgenic mouse lines deleted for CB1 receptor in adrenergic and noradrenergic neurons, CamK2a expressing neurons, and adipocytes. CB1 receptor deletion from adipocytes revealed a significant role of the brain-sensory-adipocyte axis in obesity. The data highlight the role of CB1 receptor in sympathetic activity, food intake and stress induced obesity. At the NUS lab, Raj will lead studies on the roles of activin receptors ALK4 and ALK7 in adipogeneiss, adipose tissue homeostasis and obesity. In our latest paper, we show that the p75 neurotrophin receptor p75NTR can signal very differently in diferent types of neurons. Using pharmacological and genetic techniques, we demonstrate that this is partly controlled by differential proteolytic cleavage of the receptor in different cell types. The new work has appeared online in the Journal of Cell Science. Signaling by the p75 neurotrophin receptor (p75NTR) is often referred to as cell-context dependent, but neuron-type specific signaling by p75NTR has not been systematically investigated. Here, we report that p75NTR signals very differently in hippocampal neurons (HCNs) and cerebellar granule neurons (CGNs), and present evidence indicating that this is partly controlled by differential proteolytic cleavage. NGF induced caspase-3 activity and cell death in HCNs but not in CGNs, while it stimulated NFκB activity in CGNs but not in HCNs. HCNs and CGNs displayed different patterns of p75NTRproteolytic cleavage. While the p75NTR carboxy terminal fragment (CTF) was more abundant than the intracellular domain (ICD) in HCNs, CGNs exhibited fully processed ICD with very little CTF. Pharmacological or genetic blockade of p75NTR cleavage by gamma-secretase abolished NGF-induced upregulation of NFκB activity and enabled induction of CGN death, phenocopying the functional profile of HCNs. Thus, the activities of multifunctional receptors, such as p75NTR, can be tuned into narrower activity profiles by cell-type-specific differences in intracellular processes, such as proteolytic cleavage, leading to very different biological outcomes. Read the full article HERE. The Department of Physiology of the Yong Loo Lin School of Medicine at National University of Singapore has immediate opening for postdoctoral positions in Neuroscience, with specialization in Brain Vascular Biology. As part of a University-wide initiative on mechanisms of neuronal and synaptic injury in ageing and neurodegenerative diseases under the direction of Profs. Carlos Ibanez and Edward Koo, we are seeking talented and enthusiastic individuals to join our laboratories for postgraduate training. Under the direction of Drs. Carlos Ibanez and Edward Koo, this project will focus on studies of the role of BDNF signaling in physiological and injury responses of cellular elements of the brain vascular system. More information about these laboratories can be found HERE and HERE. This is an exciting opportunity for individuals who have received a doctoral degree within the past five years and with a strong background in vascular biology or cellular neurobiology to receive further training in basic and translational studies in neurodegenerative diseases. Requirements:
Our labs are located on the Medical School campus of the National University of Singapore. There is close integration among the core laboratories of this University supported strategic initiative in neuroscience. This provides for an exciting environment to pursue neuroscience research and a great opportunity for Singaporeans, Asian expats wishing to return somewhere closer home, or anyone interested in experiencing the Asian culture, in one of the most developed and exciting countries in the region. Interested individuals should send application including cover letter, curriculum vitae, statement of research interests, and contact information, and provide names of three references to Prof. Carlos Ibanez Deadline is March 20, 2015. TGFbeta Superfamily Signaling in AdipocytesWork at Carlos Ibanez laboratory focuses on understanding the functions and signaling mechanisms of growth factors and their receptors in nervous system function and metabolic regulation, for the development of better therapies to neurodegenerative and metabolic disorders. Carlos Ibanez is Professor at the Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore. A postdoctoral fellow is currently being recruited to advance research on growth factor receptor signaling and function in metabolic regulation of fat deposition, adipose tissue function, CNS regulation of metabolism, and obesity. In our latest paper, we reported that the sensitivity of fat cells to signals that increase the breakdown of fat is linked to the TGFbeta superfamily receptor ALK7. This discovery, published recently in eLife (http://elifesciences.org/content/3/e03245), suggests that ALK7 is a promising new target for strategies to treat human obesity. We are seeking talented, innovative and enthusiastic researchers with a PhD awarded within the last 5 years to elucidate adipogenic and homeostatic functions of ALK4 and ALK7 receptors in adipose tissue to advance novel therapeutic opportunities. We will only consider candidates with documented expertise in studies of intracellular signaling pathways, with preference for TGFbeta superfamily signaling and molecular/cellular endocrinology. Candidates lacking expertise in this area will not be considered. Our group at NUS has linked up with a network of researchers studying metabolism regulation in Singapore. This provides for an exciting environment to pursue metabolism research and a great opportunity for Singaporeans, Asian expats wishing to return somewhere closer home, or anyone interested in experiencing the Asian culture, in one of the most developed and exciting countries in the region.
Applications, including CV, list of publications and statement of future interests should be sent to Prof. Carlos Ibanez ( Funding is available for an initial period of 2 to 3 years, starting any time during 2015. Deadline for application is March 1, 2015 Goh Ket Yin earned a BSc at UCSI University, Malaysia, and is MSc in Medical Biosciences from University of Bath, United Kingdom. She has solid training in cell culture and transfection techniques, western blots and immunohistochemistry. She joins to assist in animal care and handling, mice genotyping and tissue harvest. The Sunday edition of the The Straits Times publishes today an interview with Carlos Ibanez highlighting the discovery of ALK7 link to fat deposition in obesity (reported in our paper published last week in eLife). Also newspapers MyPaper and Lianhe Zaobao carry stories (in Chinese) on the ALK7 discovery. In our latest paper, we report that the sensitivity of fat cells to signals that increase the breakdown of fat is linked to the receptor ALK7. The discovery, which is published today in eLife, suggests that ALK7 is an interesting target for future strategies to treat obesity. The ALK7 receptor is predominantly found in fat cells and tissues involved in controlling the metabolism. Intriguingly, mice with a mutation in ALK7 accumulate less fat than mice with a functional version of the protein. Until now, it has not been known why. We created mice whose fat cells lack ALK7, but whose other cells all produce ALK7 as normal. We found that fat cells lacking the ALK7 receptor are more sensitive to adrenaline and noradrenaline signals, a finding that can explain why they accumulate less fat even though the mice were on a high-fat diet. Adrenaline and noradrenaline are central players in metabolism. These hormones trigger the burst of energy and increase in heart rate and blood pressure that are needed for the “fight-or-flight” response. The hormones normally stimulate the breakdown of fat, but when nutrients are plentiful, fat cells become resistant to this signal and instead store fat. This mechanism evolved to facilitate energy storage during times of abundant food supply, enhancing survival upon starvation. In the industrialized world where food is constantly accessible, this resistance can cause an unhealthy increase in body fat and result in obesity. We then investigated if it is possible to prevent obesity by blocking ALK7. At present, there are no known ALK7 inhibitors, but we solved this by generating mice with a special mutation in ALK7 which renders it sensitive to inhibition by a chemical substance. This made it possible for us to block the receptor at any time in an otherwise normal adult animal. – Using this approach, we could get these mice to be leaner on a high fat diet simply by administration of the chemical. This suggests that acute inhibition of the ALK7 receptor can prevent obesity in adult animals, says Tingqing Guo, first author of the study. We have also showed that the ALK7 receptor works in a similar way in human fat cells as it does in mice. – Overall, these results suggest that blockade of the ALK7 receptor could represent a novel strategy to combat human obesity, says Carlos Ibanez, principal investigator of the study. The work was supported by grants from the European Research Council, Swedish Research Council, Strategic Research Program in Diabetes of Karolinska Institutet, Swedish Cancer Society, Knut and Alice Wallenberg Foundation, the National University of Singapore and the National Medical Research Council of Singapore. eLife is a peer-reviewed open-access scientific journal established at the end of 2012 by Nobel Prize Winner Randy Schekman, with support from the Howard Hughes Medical Institute, Max Planck Society and Wellcome Trust. The paper is freely accessible and can be found HERE. The Academic Research Fund of the Ministry of Education of Singapore has awarded a Tier2 research grant to Carlos Ibanez Lab to support work on activation and signal decoding mechanisms of neuronal death receptors, including p75NTR. A Research Assistant is currently being recruited to our NUS laboratory. The successful candidate will be a dynamic, service-minded person, with a solid research background in molecular biology, tissue culture, histological techniques and/or mouse genetics methods. He/she will have a strong presence in the laboratory by assisting the group by with experimental lab routines, including maintenance of mouse colonies, genotyping, molecular biology and histology, as well as conducting research together with other lab members or independently. Work at the laboratory focuses on understanding the functions and signaling mechanisms of neuronal growth factors and their receptors in neural development, injury responses and metabolic regulation, for the development of better therapies to diseases of the nervous system and metabolism. Applications including CV and names plus email addresses of three referees should be sent by email before September 5 to Prof. Carlos Ibanez The National Medical Research Council (NMRC) of Singapore has awarded two research grants to Carlos Ibanez Lab to support work on i) p75 neurotrophin receptor in nervous system physiology and neurodegeneration, and ii) ALK7 signaling in metabolic regulation, respectively. The latter is in collaboration with A/Prof. Sue-Anne Toh from NUS Department of Medicine. Yong Shan May has a BSc from the University of Malaya and will be defending her PhD thesis at NUS next year with title “ApoE isoform-specific modulation of NMDA receptor signalling pathway during ageing”. She has extensive expertise in experimental neuroscience including neuron isolation, immunohistochemistry and behavioural studies. Shan May joins our group to help with mouse breeding and genotyping, as well as immunohistochemical analyses of neurons in culture and tissue sections. Diabetologia has now published online our latest paper describing differential actions of activins A and B and Smad proteins 2 and 3 on the regulation of insulin secretion by pancreatic beta cells (Wu et al., 2013). Glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells is regulated by paracrine factors whose identity and mechanisms of action are incompletely understood. Activins are expressed in pancreatic islets and have been implicated in the regulation of GSIS. Activins A and B signal through a common set of intracellular components, but it is unclear whether they display similar or distinct functions in glucose homeostasis. Glucose homeostatic responses were examined in mice lacking activin B and in pancreatic islets derived from these mutants. The ability of activins A and B to regulate downstream signalling, ATP production and GSIS in islets and in beta-cells was compared. Mice lacking activin-B displayed elevated serum insulin levels and glucose-stimulated insulin release. Injection of a soluble activin B antagonist phenocopied these changes in wild type mice. Isolated pancreatic islets from mutant mice showed enhanced GSIS which could be rescued by exogenous activin B. Activin B negatively regulated GSIS and ATP production in wild type islets, while activin-A displayed opposite effects. The downstream mediator Smad3 responded preferentially to activin B in pancreatic islets and beta-cells, while Smad2 showed preference for activin A, indicating distinct signalling effects of the two activins. In line with this, overexpression of Smad3, but not Smad2, decreased GSIS in pancreatic islets. These results reveal a tug-of-war between activin ligands in the regulation of insulin secretion by beta-cells and suggest that manipulation of activin signalling could be a useful strategy for the control of glucose homeostasis in diabetes and metabolic disease. Read the full article HERE. A Research Assistant is currently being recruited to our NUS laboratory. The successful candidate will be a dynamic, service-minded person, with a solid research background in molecular biology, tissue culture, histological techniques and/or mouse genetics methods. He/she will have a strong presence in the laboratory by assisting the group by with experimental lab routines, including maintenance of mouse colonies, genotyping, molecular biology and cell culture experiments, as well as conducting research together with other lab members or independently. Work at the laboratory focuses on understanding the functions and signaling mechanisms of neuronal growth factors and their receptors in neural development, injury responses and metabolic regulation, for the development of better therapies to diseases of the nervous system and metabolism. Applications including CV and names plus email addresses of three referees should be sent by email before October 15 to Prof. Carlos Ibanez Eddy Goh obtained a PhD in Biochemistry at University College London, UK, under the supervision of Prof. Ivan Gout for his work on the nuclear functions of ribosomal S6 kinases. He did postdoctoral studies at the University of Dundee, Scotland, under the direction of Prof. Philip Cohen. Here Eddy studied mechanisms of regulation of E3 ligases in innate immunity. At our NUS group, he will investigate the mechanisms by which p75ntr couples to the NFkB pathway and devise novel mechanism-based approaches to modulate p75 signaling with small molecules. |
RhoGDI interaction to p75NTR |
|
|||
