Carlos Ibanez leaves NUS employment and becomes NUS Visiting Professor

Prof. Carlos Ibanez leaves NUS and relocates to Beijing to attend to his new research units in Peking University and Chinese Institute for Brain Research (CIBR). He becomes NUS Visiting Professor from 01 January. The members of the NUS group continue their research activities to wrap up ongoing projects and ready their recent findings for publication. Carlos Ibanez remains affiliated with the Karolinska Institute as part time Professor in the Department of Neuroscience.

New paper defines how p75 neurotrophin receptor contributes to Alzheimer's Disease pathology by regulating APP internalization

A prevalent model of Alzheimer’s disease (AD) pathogenesis postulates the generation of neurotoxic fragments derived from the amyloid precursor protein (APP) after its internalization to endocytic compartments. The molecular pathways that regulate APP internalization and intracellular trafficking in neurons are incompletely understood.

In this paper, we report that 5xFAD mice, an animal model of AD, expressing signaling-deficient variants of the p75 neurotrophin receptor (p75NTR) show greater neuroprotection from AD neuropathology than animals lacking this receptor. p75NTR knock-in mice lacking the death domain or transmembrane Cys259 showed lower levels of Aβ species, amyloid plaque burden, gliosis, mitochondrial stress and neurite dystrophy than global knock-outs. Strikingly, long-term synaptic plasticity and memory, which are completely disrupted in 5xFAD mice, were fully recovered in the knock-in mice. Mechanistically, we found that p75NTR interacts with APP at the plasma membrane and regulates its internalization and intracellular trafficking in hippocampal neurons. Inactive p75NTR variants internalized considerably slower than wild type p75NTR and showed increased association with the recycling pathway, thereby reducing APP internalization and colocalization with BACE1, the critical protease for generation of neurotoxic APP fragments, favoring non-amyloidogenic APP cleavage. These results reveal a novel pathway that directly and specifically regulates APP internalization, amyloidogenic processing and disease progression, and suggest that inhibitors targeting the p75NTR transmembrane domain may be an effective therapeutic strategy in AD.

The paper has been published in The EMBO Journal.

Read the full paper HERE

New paper elucidates how brown adipose tissue adapts to nutrient stress

Adaptation to nutrient availability is crucial for survival. Upon nutritional stress, such as during prolonged fasting or cold exposure, organisms need to balance the feeding of tissues and the maintenance of body temperature. Mechanisms regulating the adaptation of brown adipose tissue (BAT), a key organ for non-shivering thermogenesis, to variations in nutritional state have been unknown.

In this new paper, we report that specific deletion of the activin receptor ALK7 in BAT resulted in fasting-induced hypothermia due to exaggerated catabolic activity in brown adipocytes. After overnight fasting, BAT lacking ALK7 showed increased expression of genes responsive to nutrient stress, including the upstream regulator KLF15, aminoacid catabolizing enzymes, notably proline dehydrogenase (POX), and adipose triglyceride lipase (ATGL), as well as markedly reduced lipid droplet size. In agreement with this, ligand stimulation of ALK7 suppressed POX and KLF15 expression in both mouse and human brown adipocytes. Treatment of mutant mice with the glucocorticoid receptor antagonist RU486 restored KLF15 and POX expression levels in mutant BAT, suggesting that loss of BAT ALK7 results in excessive activation of glucocorticoid signaling upon fasting. These results reveal a novel signaling pathway downstream of ALK7 which regulates the adaptation of BAT to nutrient availability by limiting nutrient stress-induced overactivation of catabolic responses in brown adipocytes

The paper has been published in eLife.

Read the full paper HERE

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 undetectable at the protein level 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, CD137 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

Carlos Ibanez starts new laboratories at Peking University and Chinese Institute for Brain Research

Starting in January 2020, new twin laboratories dedicated to studies of growth factor receptor signaling and physiology will be established at the McGovern Institute of the School of Life Sciences in Peking University, and the Chinese Institute for Brain Research in Beijing, China. The research activities of the PKU and CIBR labs will run in parallel to and complement with those ongoing at the KI and NUS laboratories. The initial focus of the new labs will be on studies of death receptor signaling in neurodegeneation, metabolic regulation by activin receptors ALK4 and ALK7, and control of brain microvasculature integrity and function by neurotrophin signaling. PhD students, postdoctoral fellows and lab technicians are being recruited for the new Beijing laboratories. Follow developments in the PKU and CIBR labs at 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.

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