Open Postdoctoral Position: Molecular / Cellular Neurobiologists

We are seeking talented and enthusiastic researchers with expertise in molecular and cellular neuroscience to advance investigations on the functions and mechanisms of growth factor receptor signaling and physiology in the nervous system. The research entails studies of different receptor systems in neuronal and nervous system function using molecular methods, cell culture models and mutant mice carrying specific mutations in these receptors.

Candidates will be accepted at the postdoctoral level with a PhD awarded preferably within the last 5 years. Strong and documented expertise in molecular and cellular methods of analysis as applied to studies of intracellular signaling in the area of neuroscience is an absolute requirement for consideration. Successful applicants shall be well versed in primary cultures of different neuronal populations from the mouse brain. The successful candidate is expected to be sufficiently independent to formulate questions, design experiments and perform research. For more information and publications, please look HERE in our lab website.

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

Deadline for application is 20 June 2019.

Funding is available for an initial period of 3 years, with start during 2019.

New paper reports unexpected convergence of TDP-43 and BDNF signaling hubs in regulation of synaptic plasticity, learning and memory

In this new paper, we report that abnormal TDP‐43 function culminate in impaired secretion of the neurotrophin BDNF, whose restoration is sufficient to rescue major disease phenotypes caused by aberrant TDP‐43 activity.

Aberrant function of the RNA‐binding protein TDP‐43 has been causally linked to multiple neurodegenerative diseases. Due to its large number of targets, the mechanisms through which TDP‐43 malfunction cause disease are unclear. Here, we report that knockdown, aggregation, or disease‐associated mutation of TDP‐43 all impair intracellular sorting and activity‐dependent secretion of the neurotrophin brain‐derived neurotrophic factor (BDNF) through altered splicing of the trafficking receptor Sortilin. Adult mice lacking TDP‐43 specifically in hippocampal CA1 show memory impairment and synaptic plasticity defects that can be rescued by restoring Sortilin splicing or extracellular BDNF. Human neurons derived from patient iPSCs carrying mutated TDP‐43 also show altered Sortilin splicing and reduced levels of activity‐dependent BDNF secretion, which can be restored by correcting the mutation. We propose that major disease phenotypes caused by aberrant TDP‐43 activity may be explained by the abnormal function of a handful of critical proteins, such as BDNF.

The paper has just been published in The EMBO Journal.

Read the full paper HERE.

Two new Senior Research Fellows join NUS group

Lilian Kisiswa obtained a PhD in 2011 in Visual Neursocience at Cardiff University, UK, under the direction of Prof. James E Morgan. Her PhD thesis was entitled “The role of inhibitor of apoptosis (IAPs) in retinal ganglion cell death and dendrite remodelling“. She then did postdoctoral studies at the Department of Molecular Biosciences, School of Biosciences, Cardiff University, under the direction of Prof. Alun M Davies. Lilian joined our Stockholm team at Karolinska Institue in August 2013 to investigate the interplay between RIP2 and TRAF6 in p75NTR signaling. Her work led to a publication in Cell Reports. She now joins our NUS team to continue work on p75NTR and RhoA signaling.

Marta Garcia-Miralles obtained her PhD in 2013 at the Department of Neurodegenerative Diseases, Hertie Institute for Clinical Brain Research, University of Tuebingen, Germany, under the direction of Prof. Thomas Gasser, and with the characterisation of a novel LRRK2 mouse model of Parkinson’s disease. She then worked as a postdoc fellow at the Translational Laboratory in Genetic Medicine (TLGM), A*STAR, Singapore, under the direction of Dr. Mahmoud Pouladi. She is joining our NUS team to contribute to our efforts to understand the roles of neurotrophin signaling in cerebrovascular disease.

Singapore media highlights identification of small molecule targeting the transmembrane domain of death receptor p75NTR

The Saturday edition of the The Straits Times publishes today an interview with Carlos Ibanez highlighting the identification a small molecule targeting the transmembrane domain of death receptor p75NTR that induces melanoma cell death and reduces tumor growth (reported in our paper published in Cell Chemical Biology). Read the full article here. Also newspaper Lianhe Zaobao (Chinese Daily) carried a story (in Chinese) on the discovery.

New paper reports the identification of a small molecule targeting the transmembrane domain of death receptor p75NTR

In this new paper, we have used a novel chemical biology approach to identify a small molecule targeting the transmembrane domain of death receptor p75NTR that induces melanoma cell death and reduces tumor growth

Small molecules offer powerful ways to alter protein function. However, most proteins in the human proteome lack small-molecule probes, including the large class of non-catalytic transmembrane receptors, such as death receptors. We hypothesized that small molecules targeting the interfaces between transmembrane domains (TMDs) in receptor complexes may induce conformational changes that alter receptor function. Applying this concept in a screening assay, we identified a compound targeting the TMD of death receptor p75<sup>NTR</sup> that induced profound conformational changes and receptor activity. The compound triggered apoptotic cell death dependent on p75<sup>NTR</sup> and JNK activity in neurons and melanoma cells, and inhibited tumor growth in a melanoma mouse model. Due to their small size and crucial role in receptor activation, TMDs represent attractive targets for small-molecule manipulation of receptor function.

The paper has just been published in Cell Chemical Biology.

Read the full paper HERE.

Postdoctoral Positions in Growth Factor Receptor Signaling and Physiology: NUS, Singapore and KI, Sweden

We are seeking talented and enthusiastic researchers with expertise in cell signaling, cell biology and mouse genetics to advance investigations on the functions and mechanisms of growth factor receptor signaling and physiology. The research entails studies of different receptor systems, including death receptor p75NTR, TGFbeta superfamily receptor ALK7 and neurotrophin receptor TrkB, using molecular methods, cell culture models and mutant mice carrying specific mutations in these receptors. Please refer to our recent list of publications in this areas.

Candidates will be accepted at the postdoctoral level with a PhD awarded preferably within the last 5 years. Strong and documented expertise in cellular, molecular and histological methods as applied to studies of mouse models in the areas of either neurobiology, metabolic regulation or cancer is a requirement for consideration. The successful candidate is expected to be sufficiently independent to formulate questions, design experiments and perform research.

We are recruiting fellows for our laboratories at the National University of Singapore and the Karolinska Institute in Stockholm, Sweden. Interested applicants can apply to both locations or just one. Work at the two laboratories is seamlessly integrated through joint lab meetings, common reagent and protocol records, and other cloud-based tools. Both sites provide exciting environments to pursue biomedical research at the highest level and a great opportunity to advance a career in science in exciting locations in Europe and Asia.

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

Applications will be considered as they arrive until the positions are filled. Interested applicants are strongly recommended to submit their applications as soon as possible. Funding is available for an initial period of 3 to 4 years, starting any time during 2018 or early 2019.

New paper shows how RIP2 and TRAF6 compete for binding to p75NTR and regulate neuronal cell death

In this new paper, we show how intracellular effectors RIP2 and TRAF6 compete for binding to the p75NTR intracellular domain to regulate cell death of cerebellar granule neurons.

Cerebellar granule neurons (CGNs) undergo programmed cell death during the first postnatal week of mouse development, coincident with sustained expression of the death receptor p75NTR. Although ablation of p75NTR did not affect CGN cell death, deletion of the downstream effector RIP2 significantly increased CGN apoptosis, resulting in reduced adult CGN number and impaired behaviors associated with cerebellar function. Remarkably, CGN death was restored to basal levels when p75NTR is deleted in RIP2-deficient mice. We found that RIP2 gates the signaling output of p75NTR by competing with TRAF6 for binding to the receptor intracellular domain. In CGNs lacking RIP2, more TRAF6 was associated with p75NTR, leading to increased JNK-dependent apoptosis. In agreement with this, pharmacological inhibition or genetic ablation of TRAF6 restored cell death levels in CGNs lacking RIP2. These results revealed an unexpected mechanism controlling CGN number and highlight how competitive interactions govern the logic of death receptor function.

The paper has just been published in Cell Reports.

Read the full paper HERE.

New paper reveals cell-autonomous role of GFRα1 in the development of olfactory bulb GABAergic interneurons

In this new paper, we show how the GDNF receptor GFRα1 functions cell-autonomously in subpopulations of olfactory bulb interneuron precursors to regulate their generation and allocation in the mammalian olfactory bulb.

GFRα1, a receptor for glial cell line-derived neurotrophic factor (GDNF), is critical for the development of the main olfactory system. The olfactory bulb (OB) of Gfra1 knockout mice showed significant reductions in the number of olfactory sensory neurons, mitral and tufted cells, as well as all major classes of OB GABAergic interneurons. However, the latter did not express significant levels of GFRα1, leaving the mechanism of action of GFRα1 in OB interneuron development unexplained. We have found that GFRα1 is highly expressed in the precursor cells that give rise to all major classes of OB interneurons, but is downregulated as these neurons mature. Conditional ablation of GFRα1 in embryonic GABAergic cells recapitulated the cell losses observed in global Gfra1 knockouts at birth. GFRα1 was also required for the sustained generation and allocation of OB interneurons in adulthood. Conditional loss of GFRα1 altered the migratory behaviour of neuroblasts along the rostral migratory stream (RMS) as well as RMS glial tunnel formation. Together, these data indicate that GFRα1 functions cell-autonomously in subpopulations of OB interneuron precursors to regulate their generation and allocation in the mammalian OB.

The paper has just been published in Biology Open.

Read the full paper HERE.

Jason Tann defends PhD thesis work and is now Dr. Jason

Jason has successfully defended his thesis today titled “Understanding The Influence Of TDP-43 Loss-Of-Function On Neurotrophin Signalling”. Committee members Soong Tuck Wah, Garrie Arumugam and John Chua had a closed door session with him after the presentation, but we hear that it all went well. Congratulations to Dr. Jason!

Carlos Ibanez presents the Nobel Prize in Physiology or Medicine 2017

Presentation Speech by Professor Carlos Ibáñez, Member of the Nobel Assembly at the Karolinska Institute, Member of the Nobel Committee for Physiology or Medicine, at the award ceremony of the Nobel Prize, 10 December 2017.

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.

New paper reveals how GDNF controls survival of molecular layer interneurons in the cerebellum

In this new paper, we show how the GDNF regulates survival of molecular layer interneurons in the cerebellum to control normal cerebellar motor learning. The paper has just been published in Cell Reports.

The role of neurotrophic factors as endogenous survival proteins for brain neurons remains contentious. In the cerebellum, the signals controlling survival of molecular layer interneurons (MLIs) are unknown, and direct evidence for the requirement of a full complement of MLIs for normal cerebellar function and motor learning has been lacking. Here, we show that Purkinje cells (PCs), the target of MLIs, express the neurotrophic factor GDNF during MLI development and survival of MLIs depends on GDNF receptors GFRα1 and RET. Conditional mutant mice lacking either receptor lose a quarter of their MLIs, resulting in compromised synaptic inhibition of PCs, increased PC firing frequency, and abnormal acquisition of eyeblink conditioning and vestibulo-ocular reflex performance, but not overall motor activity or coordination. These results identify an endogenous survival mechanism for MLIs and reveal the unexpected vulnerability and selective requirement of MLIs in the control of cerebellar-dependent motor learning.

Read the full paper HERE.

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.

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