New Research Fellow joins NUS group to lead drug discovery efforts for transmembrane receptors

Vanessa Rodrigues holds a PhD in Pathology and Molecular Genetics from ICBAS, University of Porto, Portugal, with a thesis work entitled “Understanding P-glycoprotein mediated multidrug resistance in cancer: new potential targets, biomarkers and molecular inhibitors”.  Vanessa joins the NUS group to lead a drug discovery program to identify novel chemical probes targeting p75NTR, TrkB and ALK7 receptors.

 

New Research Fellow joins NUS group to investigate p75NTR signaling mechanisms

Ajeena Ramanujan holds a PhD from the Jawaharlal Nehru University, India, for work on the interaction between FZR1 and the Retinoblastoma protein in the control of cell-cycle regulation, under the direction of A/Prof Swati Tiwari. Ajeena is joining the NUS group to lead investigations on p75NTR signaling mechanisms involving RhoGDI and RhoA proteins and their actions on the cell cytoskeleton and neurite outgrowth control.

Joint retreat of NUS and KI labs in Singapore

Fellows from the KI lab flew to Singapore for a 2 day retreat with the NUS group on 16th and 17th of January 2017. After 4 years of joint lab meetings over Skype, fellows of both groups enjoyed an opportunity to discuss common projects and ideas face to face. We were joined by the NUS and UCSD groups of Prof. Ed Koo and had joint plenary and also parallel sessions, as well as group building activities, as shown in the photo below.

 

Open Postdoctoral Positions

UPDATE 2017-05-29: The positions have been filled. 

Postdoc/Research Fellows are being recruited to our NUS laboratory. We are seeking talented, innovative and enthusiastic researchers with a PhD awarded within the last 5 years.

Cell signaling

The successful candidate will have a strong background in studies of cell signaling using molecular, cellular and biochemical methods. The aim of the project is to elucidate mechanisms of differential signaling by death receptors through the NFkB, c-Jun kinase and RhoA GTPase pathways, among others, taking advantage of recent knowledge on structure-function relationships in this class of receptors as well as a large collection of mutants developed at our laboratory. Strong expertise in cell and molecular biology techniques is essential. Additional expertise in live cell imaging will also be an asset to the project.

Drug Discovery

The successful candidate will have a strong background in studies of intracellular signaling involving biochemical assays, gene reporter assays and microscopy techniques. The aim of the project is the identification and characterisation of novel small molecule modulators (inhibitors and activators) of growth factor receptor signaling taking advantage of a novel screening strategy developed in the laboratory based on recent knowledge on the mechanisms of activation and downstream signal propagation of death receptors and receptors of the TGFb superfamily. Strong expertise in cell and molecular biology techniques is essential. Additional expertise in small molecule screening and/or chemistry will also be an asset to the project.

Applications, including CV, list of publications and statement of future interests should be sent to Prof. Carlos Ibanez . Applicants should arrange to have at least two confidential letters of reference sent independently by referees to this email address.

Funding is available for an initial period of 2 to 3 years, starting any time during 2017.

Deadline for the application is March 07, 2017.

New paper shows novel function of the GFRα1 receptor

In this new paper, we show how the GFRα1 receptor regulates Purkinje cell migration independently of GDNF or RET, by limiting the function of NCAM. The paper has just been published in Cell Reports.

During embryonic development of the cerebellum, Purkinje cells (PCs) migrate away from the ventricular zone to form the PC plate. The mechanisms that regulate PC migration are incompletely understood. Here, we report that the neurotrophic receptor GFRα1 is transiently expressed in developing PCs and loss of GFRα1 delays PC migration. Neither GDNF nor RET, the canonical GFRα1 ligand and co-receptor, respectively, contribute to this process. Instead, we found that the neural cell adhesion molecule NCAM is co-expressed and directly interacts with GFRα1 in embryonic PCs. Genetic reduction of NCAM expression enhances wild-type PC migration and restores migration in Gfra1 mutants, indicating that NCAM restricts PC migration in the embryonic cerebellum. In vitro experiments indicated that GFRα1 can function both in cis and trans to counteract NCAM and promote PC migration. Collectively, our studies show that GFRα1 contributes to PC migration by limiting NCAM function.

Read the full paper HERE.

New paper shows how thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons

In our latest paper, we show how thalamo-cortical axons regulate the radial dispersion of neocortical GABAergic interneurons. The paper has just been published in eLife.

Neocortical GABAergic interneuron migration and thalamo-cortical axon (TCA) pathfinding follow similar trajectories and timing, suggesting they may be interdependent. The mechanisms that regulate the radial dispersion of neocortical interneurons are incompletely understood. In this new study we report that disruption of TCA innervation, or TCA-derived glutamate, affected the laminar distribution of GABAergic interneurons in mouse neocortex, resulting in abnormal accumulation in deep layers of interneurons that failed to switch from tangential to radial orientation. Expression of the KCC2 cotransporter was elevated in interneurons of denervated cortex, and KCC2 deletion restored normal interneuron lamination in the absence of TCAs. Disruption of interneuron NMDA receptors or pharmacological inhibition of calpain also led to increased KCC2 expression and defective radial dispersion of interneurons. Thus, although TCAs are not required to guide the tangential migration of GABAergic interneurons, they provide crucial signals that restrict interneuron KCC2 levels, allowing coordinated neocortical invasion of TCAs and interneurons.

Read the full paper HERE. (Supplemental information 31.6MB)

Two new Research Assistants join NUS group

Shuhailah Salim holds a Bachelor in Science from Nanyang Technological University. She did a research internship at the Institute of Molecular and Cell biology (IMCB, A*STAR). She joins our NUS group to support biochemical, tissue culture and drug screening studies.

New Chih Sheng holds a Bachelor in Science from the University of Toronto. He did a research internship at the Institute of Molecular and Cell biology (IMCB, A*STAR). She joins our NUS group to support our metabolism research projects with mouse genotyping and tissue culture.

New Research Fellow joins NUS group to investigate p75NTR-mediated neurodegeneration mechanisms

Yi Chenju holds a Bachelor in Clinical Medicine from Tongji Medical College, Huazhong University of Science and Technology, China, a PhD in Neurology form the same institution and an MD from the Institute of Brain Research, University of Tübingen, Germany. She performed postdoctoral studies at College de France under the direction of Drs. Christian Gaume and Annette Koulakoff. Chenju is joining the NUS group to lead investigations on p75NTR-mediated mechanisms of neurodegeneration in mouse models of Alzheimer’s disease.

 

New paper demonstrates requirement of p75NTR death domain and transmembrane cysteine for neuronal death in the CNS

In our latest paper, we show how dimers of the p75NTR neurotrophin receptor are indipensable for p75NTR-mediated cell death in the central nervous system. The paper has justg been published in the Journal of Neuroscience.

The oligomeric state and activation mechanism that enable p75 NTR to mediate these effects have recently been called into question. In this new study, we have investigated mutant mice lacking the p75NTR death domain (DD) or a highly conserved transmembrane (TM) cysteine residue (Cys 259) implicated in receptor dimerization and activation. Neuronal death induced by proneurotrophins or epileptic seizures was assessed and compared with responses in p75NTR knock-out mice and wild-type animals. Proneurotrophins induced apoptosis of culturedhippocampalandcorticalneuronsfromwild-typemice,butmutantneuronslackingp75NTR,onlythep75NTR DD,orjustCys259 were all equally resistant to proneurotrophin-induced neuronal death. Homo-FRET anisotropy experiments demonstrated that both NGF and proNGF induce conformational changes in p75 NTR that are dependent on the TM cysteine. In vivo, neuronal death induced by pilocarpine-mediated seizures was significantly reduced in the hippocampus and somatosensory, piriform, and entorhinal cortices of all three strains of p75 NTR mutant mice. Interestingly, the levels of protection observed in mice lacking the DD or only Cys 259 were identical to those of p75 NTR knock-out mice even though the Cys 259 mutant differed from the wild-type receptor in only one amino acid residue. We conclude that,bothinvitroandinvivo,neuronaldeathinducedbyp75NTR requirestheDDandTMCys259,supportingthephysiological relevance of DD signaling by disulfide-linked dimers of p75NTR in the CNS.

Read the full paper HERE.

Open position: Research Assistant

UPDATE 01-06-2016: The position has been filled.

A Research Assistant/Associate is currently being recruited to our laboratory in the Centre for Life Sciences, National University of Singapore, Kent Ridge 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 with experimental lab routines as well as conducting research together with other lab members or independently, including:

  • maintenance of mouse colonies and genotyping
  • histological studies
  • molecular biology studies
  • tissue culture studies

Applications including CV  and names plus email addresses of three referees should be sent by email to Prof. Carlos Ibanez 

Deadline: MAY 21st, 2016

Open position: Postdoctoral fellow in Neuroscience

UPDATE 2016-04-11: The position has been filled. 

As part of a University-wide initiative on mechanisms of neuronal and synaptic injury in aging and neurodegenerative diseases, we are seeking talented and enthusiastic individuals to join our laboratory.

Carlos Ibanez is Professor at the Department of Physiology, Yong Loo Lin School of Medicine, National Univeristy of Singapore, and Department of Neuroscience, Karolinska Institute, Stockholm, Sweden.

Under the direction of Prof. Carlos Ibanez, this project will focus on studies of the role of neurotrophin signaling in neurodegenerative diseases, with afocus on Alzheimer’s disease and dementias. This is an exciting opportunity for individuals who have received a doctoral degree within the past five years and with a strong background in cellular neurobiology. Other requirements include i) experience on mouse models, i i) experience in neurohistological methods, and iii) ability to work independently with precision and good organizational skills. Located on the Medical School campus of the National University of Singapore, there is close integration among the core laboratories of this strategic initiative. This provides for an exciting environment to pursue neuroscience research and a great opportunity in one of the most developed and exciting countries in the region.

Applications including CV and names plus email addresses of three referees should be sent by email  to Prof. Carlos Ibanez .

Deadline: MARCH 31, 2016

New review article published: Biology of GDNF and its receptors — Relevance for disorders of the central nervous system

A targeted effort to identify novel neurotrophic factors for midbrain dopaminergic neurons resulted in the isolation of GDNF (glial cell line-derived neurotrophic factor) from the supernatant of a rat glial cell line in 1993. Over two decades and 1200 papers later, the GDNF ligand family and their different receptor systems are now recognized as one of the major neurotrophic networks in the nervous system, important for the devel- opment, maintenance and function of a variety of neurons and glial cells. The many ways in which the four mem- bers of the GDNF ligand family can signal and function allow these factors to take part in the control of multiple types of processes, from neuronal survival to axon guidance and synapse formation in the developing nervous system, to synaptic function and regenerative responses in the adult. In this review, recently published in Neurobiology Of Disease, basic aspects of GDNF signaling mechanisms and receptor systems are first summarized followed by a review of current knowledge on the physiology of GDNF activities in the central nervous system, with an eye to its relevance for neurodegenerative and neuropsychiatric diseases. Read the full paper HERE.

NMRC award to Carlos Ibanez Lab for metabolism work

The National Medical Research Council of Singapore has awarded a Collaborative Basic Research Grant (CBRG) to Carlos Ibanez for investigations into novel pathways controlling metabolic functions in adipose tissue. The award includes collaborative projects with Han Weiping, from the Singapore Bioimaging Consortium at ASTAR, Neerja Karnani, from the Singapore Institue for Clinical Sciences, and Asim Shabbir, from the National University Hospital of Singapore.

NUS, UCL, KI Neuroscience Workshop 2016

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.

New paper describes first structures of protein complexes of the p75NTR death domain

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 Research Fellow Lin Zhi takes up group leader position at Tianjin University

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!

New Research Assistant joins NUS group

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.

Two new Research Fellows join NUS group

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.

Research Assistant/Associate position open

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.

New Senior Research Fellow joins NUS group to launch metabolism programme

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.

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Death Domain Signaling by Disulfide-Linked Dimers of the p75 Neurotrophin Receptor Mediates Neuronal Death in the CNS

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