New paper reveals that the widely used beige-adipocyte marker, CD137, negatively regulates “browning” of white adipose tissue during cold exposure

In this new paper, we report that CD137, a cell surface protein used in several studies as a marker for beige adipocytes, is detectable at the protein in beige adipocytes in vivo or in vitro, and its expression is not upregulated by adrenergic stimulation or cold exposure, as expected for a beige cell marker. Moreover, CD1377 knock-out mice showed elevated levels of thermogenic markers, including UCP1, increased numbers of beige adipocyte precursors, and expanded UCP1-expressing cell clusters in inguinal WAT after chronic cold exposure. CD137 knock-out mice also showed enhanced cold resistance. These results indicate that CD137 functions as a negative regulator of “browning” in white adipose tissue, and call into question the use of this protein as a functional marker for beige adipocytes.

The paper has just been published in  The Journal of Biological Chemistry.

Read the full paper HERE

New grant awarded by Singapore National Research Foundation (NRF) and Israel Science Foundation (ISF) to Carlos Ibanez Lab and Mike Fainzilber Lab (Weizmann Institute) for collaborative research into neurotrophin retrograde signaling

The National Research Foundation of Singapore (NRF) and Israel Science Foundation (ISF) have awarded a Collaborative Research Grant to Carlos Ibanez (NUS) and Mike Fainzilber (Weizmann Institute) for investigations into retrograde signaling by neurotrophins.

New paper reports how ALK4 coordinates extracellular signals and transcriptional programs to regulate development of cortical somatostatin interneurons

In this new paper, we report how the activin receptor ALK4 coordinates signaling by activin ligands with intrinsic transcriptional programs driven by SATB1 to regulate the development of somatostatin interneurons in the developing mouse neocortex.

Although the role of transcription factors in fate specification of cortical interneurons is well established, how these interact with extracellular signals to regulate interneuron development is poorly understood. Here we show that the activin receptor ALK4 is a key regulator of the specification of somatostatin interneurons. Mice lacking ALK4 in GABAergic neurons of the medial ganglionic eminence (MGE) showed marked deficits in distinct subpopulations of somatostatin interneurons from early postnatal stages of cortical development. Specific losses were observed among distinct subtypes of somatostatin+/Reelin+ double-positive cells, including Hpse+ layer IV cells targeting parvalbumin+interneurons, leading to quantitative alterations in the inhibitory circuitry of this layer. Activin-mediated ALK4 signaling in MGE cells induced interaction of Smad2 with SATB1, a transcription factor critical for somatostatin interneuron development, and promoted SATB1 nuclear translocation and repositioning within the somatostatin gene promoter. These results indicate that intrinsic transcriptional programs interact with extracellular signals present in the environment of MGE cells to regulate cortical interneuron specification.

The paper has just been published in The Journal of Cell Biology .

Read the full paper HERE.

New MOE Tier 2 grant awarded to Carlos Ibanez Lab for research into crosstalk between TDP43 and neurotrophic signaling

The National Medical Research Council of Singapore has awarded a Open Fund – Individual Research Grant (OF-IRG) to Carlos Ibanez for investigations into novel drug discovery methods targeting receptor transmembrane domains. The award includes collaborative projects with Profs. Yang Daiwen , from the Department of Biological Sciences (NUS), and Ang Wee Han, from the Department of Chemistry (NUS).

New NMRC grant award to Carlos Ibanez Lab for drug discovery research

The National Medical Research Council of Singapore has awarded a Open Fund – Individual Research Grant (OF-IRG) to Carlos Ibanez for investigations into novel drug discovery methods targeting receptor transmembrane domains. The award includes collaborative projects with Profs. Yang Daiwen , from the Department of Biological Sciences (NUS), and Ang Wee Han, from the Department of Chemistry (NUS).

Open Postdoctoral Position: Molecular / Cellular Neurobiologists

UPDATE July 2019: The positions have been filled. 

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.

New grant from Therapeutics Development Review Grant (TDR) awarded to Carlos Ibanez Lab for drug discovery research

The Biomedical Research Council of Singapore (ASTAR) has awarded a Therapeutics Development Review Grant (TDR) to Carlos Ibanez for investigations into novel drug discovery methods targeting receptor transmembrane domains.

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

UPDATE: The positions have been filled. 

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.

 

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