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.

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