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.

Featured article

RIP2 Gates TRAF6 Interaction with Death Receptor p75NTR to Regulate Cerebellar Granule Neuron Survival

Articles by topic

Visitors