Theses

New postdoc fellow joins KI group to study roles of p75NTR signaling in neuron survival and differentiation

Shounak Baksi obtained his PhD at the University of Calcutta, India, in September 2009. His thesis work focused on studies of alterations in Growth Factor Receptor Protein Binding Protein 2 (Grb2) signaling in Huntington’s disease cell model. His postdoctoral studies in Case Western Reserve University, Cleveland, OH, under the direction of Dr. Neena Singh,  focused on the role of Parkinson’s disease protein alpha synuclein in retinal and brain iron homeostasis. Shounak established the role of alpha synuclein in the process of transferrin receptor endocytosis. Shounak joins the KI team to pursue studies of p75 signaling mutant mice.

Change of Department affiliation

Carlos Ibanez’s team is now under the Department of Cell and Molecular Biology (CMB) of Karolinska Institute. Although the group was since 1996 under the Department of Neuroscience, its laboratories were already located at CMB space since 2004. This administrative change completes the integration of the Ibanez team in the CMB organization, in preparation for the big move to the new Biomedicum building next year.

Open Position: Cellular Electrophysiologist

UPDATE 2017-05-29: Position still open. 

We are seeking a talented and enthusiastic researcher with expertise in cellular electrophysiology to advance investigations on the functions and mechanisms of neurotrophic signaling networks in the adult nervous system. The research entails functional assessment of neuronal circuits in the brains of mutant mice lacking different neurotrophic factor receptors in specific subpopulations of neurons.

Candidates will be accepted at the postdoctoral level with a PhD awarded preferably within the last 5 years. Strong and documented expertise in electrophysiological methods as applied to studies of the rodent central nervous system, such as electrophysiological recordings from brain slices, is a requirement for consideration. Experience on calcium imaging would be an advantage.

The successful candidate is expected to be sufficiently independent to set up electrophysiological methods at our laboratory, including supervision of purchase, installation and maintenance of the necessary equipment.

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 3 to 4 years, starting any time during 2017.

Open Postdoctoral Position: Molecular / Cellular Neurobiologists

UPDATE 2017-05-29: The position has been filled. 

We are seeking a talented and enthusiastic researcher with expertise in molecular and cellular neurobiology to advance investigations on the functions and mechanisms of neurotrophic signaling in the nervous system. The research entails studies of death receptor signaling pathways in cell culture models as well as phenotypic characterisation of mutant mice carrying specific mutations in neurotrophic factor receptors. Please refer to our recent list of publications in this area HERE.

Candidates will be accepted at the postdoctoral level (PhD awarded within the last 5 years). Strong and documented expertise in cellular, molecular and histological methods as applied to studies of the rodent nervous system is a requirement for consideration. Experience with genetically modified mice is highly desirable. The successful candidate is expected to be sufficiently independent to formulate questions, design experiments and perform research.

Our group belongs to a network of laboratories dedicated to different aspects of neuroscience research and provides a strong environment for scientific growth and career development.

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 3 years, starting any time during 2017.

Deadline for application is March 7, 2017.

Joint retreat of KI and NUS 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.

 

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)

Swedish Research Council awards new research grant to Carlos Ibanez Lab

The Swedish Research Council (Vetenskapsrådet) has awarded a new grant to our KI group for work on neurotrophic signaling in the adult nervous system and its importance for neuropsychiatric disorders. Tack för förtroendet!

Carlos Ibanez named Weston Visiting Professor at the Weizmann Institute of Science

The Weizmann Institute in Israel has named Carlos Ibanez Weston Visiting Professor in the Faculty of Biochemistry, Department of Biomolecular Sciences for 3 years, starting October 2016 to conduct educational and research activities.

New lab technician joins KI group to help with histology and imaging

Wei Wang has a BSc in Public Health from Medical College of Southeast University, Nanjing, China, and a MSc in Environmental Toxicology from Shanghai Medical College, Fudan University, Shanghai, China. She has worked as Assistant Researcher at the Shanghai Institute of Applied Physics, Shanghai Institutes for Biological Sciences and the University of Gothenburg in Sweden. She joins our group to assist with histological methods and imaging of tissue samples from our mouse models.

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 just 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 cultured hippocampal and cortical neurons from wild-type mice, but mutant neurons lacking p75NTR, only the p75NTR DD, or just Cys259 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, both in vitro and in vivo, neuronal death induced by p75NTR requires the DD and TM Cys259, supporting the physiological relevance of DD signaling by disulfide-linked dimers of p75NTR in the CNS.

Read the full paper HERE.

Open position: Laboratory technician - Histology

UPDATE 2016-05-25: The position has been filled. 

We are seeking a laboratory technician to help us with histological studies of our lines of mutant mice. The candidates should have documented expertise in histological techniques, including tissue sectioning, immunohistochemistry and microscopy. Experience in histological analysis of nervous tissue is preferred. This is a project employment for a period of up to 2 years.

Application, including CV and reference names of two latest project supervisors should be sent to Prof. Carlos Ibanez

Deadline for application is 29th April, 2016

New review article published: Biology of GDNF and its receptors — Relevance for disorders of the central nervous system

A targeted effort to identify novel neurotrophic factors for midbrain dopaminergic neurons resulted in the isolation of GDNF (glial cell line-derived neurotrophic factor) from the supernatant of a rat glial cell line in 1993. Over two decades and 1200 papers later, the GDNF ligand family and their different receptor systems are now recognized as one of the major neurotrophic networks in the nervous system, important for the devel- opment, maintenance and function of a variety of neurons and glial cells. The many ways in which the four mem- bers of the GDNF ligand family can signal and function allow these factors to take part in the control of multiple types of processes, from neuronal survival to axon guidance and synapse formation in the developing nervous system, to synaptic function and regenerative responses in the adult. In this review, recently published in Neurobiology Of Disease, basic aspects of GDNF signaling mechanisms and receptor systems are first summarized followed by a review of current knowledge on the physiology of GDNF activities in the central nervous system, with an eye to its relevance for neurodegenerative and neuropsychiatric diseases. Read the full paper HERE.

New paper describes first structures of protein complexes of the p75NTR death domain

Our latest paper describes new NMR structures of the death domain in complex with downstream interactions RhoGDI and RIP2 as well as the death domain dimer. These are the first structural insights into p75NTR signaling and reveal many surprises for the death domain superfamily. The paper is now available online at eLife

Death domains (DDs) mediate assembly of oligomeric complexes for activation of downstream signaling pathways through incompletely understood mechanisms. We report structures of complexes formed by the DD of p75 neurotrophin receptor (p75NTR) with RhoGDI, for activation of the RhoA pathway, with caspase recruitment domain (CARD) of RIP2 kinase, for activation of the NF-kB pathway, and with itself, revealing how DD dimerization controls access of intracellular effectors to the receptor. RIP2 CARD and RhoGDI bind to p75NTR DD at partially overlapping epitopes with over 100-fold difference in affinity, revealing the mechanism by which RIP2 recruitment displaces RhoGDI upon ligand binding. The p75NTR DD forms non-covalent, low-affinity symmetric dimers in solution. The dimer interface overlaps with RIP2 CARD but not RhoGDI binding sites, supporting a model of receptor activation triggered by separation of DDs. These structures reveal how competitive protein-protein interactions orchestrate the hierarchical activation of downstream pathways in non-catalytic receptors.

Cancerfonden awards new research grant to Carlos Ibanez Lab

The Swedish Cancer Society (Cancerfonden) has awarded a new grant to our KI group for work on ALK7, p75 and GDNF signalling and biology. Tack för förtroendet!

Carlos Ibanez named Visiting Professor at the University of Palermo

The University of Palermo in Italy has named Carlos Ibanez  Visiting Professor at the Department of Experimental Biomedicine and Clinical Neuroscience, starting September 2015 to participate in research and didactic activities.

Mechanism for neuron-type-specific signaling by the p75NTR death receptor unravelled

In our latest paper, we show that the p75 neurotrophin receptor p75NTR can signal very differently in diferent types of neurons. Using pharmacological and genetic techniques, we demonstrate that this is partly controlled by differential proteolytic cleavage of the receptor in different cell types. The new work has appeared online in the Journal of Cell Science

Signaling by the p75 neurotrophin receptor (p75NTR) is often referred to as cell-context dependent, but neuron-type specific signaling by p75NTR has not been systematically investigated. Here, we report that p75NTR signals very differently in hippocampal neurons (HCNs) and cerebellar granule neurons (CGNs), and present evidence indicating that this is partly controlled by differential proteolytic cleavage. NGF induced caspase-3 activity and cell death in HCNs but not in CGNs, while it stimulated NFκB activity in CGNs but not in HCNs. HCNs and CGNs displayed different patterns of p75NTRproteolytic cleavage. While the p75NTR carboxy terminal fragment (CTF) was more abundant than the intracellular domain (ICD) in HCNs, CGNs exhibited fully processed ICD with very little CTF. Pharmacological or genetic blockade of p75NTR cleavage by gamma-secretase abolished NGF-induced upregulation of NFκB activity and enabled induction of CGN death, phenocopying the functional profile of HCNs. Thus, the activities of multifunctional receptors, such as p75NTR, can be tuned into narrower activity profiles by cell-type-specific differences in intracellular processes, such as proteolytic cleavage, leading to very different biological outcomes. Read the full article HERE.

And here we are...

Ibanez-lab_2015

Left: Annika, Sabrina, Maritina, Karima, Nuria, Favio
Right: Lilian, Christina, Diana, Patricia, Petronella, Claire

New method for topographic transcriptome mapping of the mouse brain

In our latest paper, we demonstrate that spatially resolved RNA-seq is ideally suited for high resolution topographical mapping of genome-wide gene expression in heterogeneous anatomical structures such as the mammalian central nervous system. The work has  appeared online in Genome Biology

Cortical interneurons originating from the medial ganglionic eminence, MGE, are among the most diverse cells within the CNS. Different pools of proliferating progenitor cells are thought to exist in the ventricular zone of the MGE, but whether the underlying subventricular and mantle regions of the MGE are spatially patterned has not yet been addressed. In this work, we combined laser-capture microdissection and multiplex RNA-sequencing to map the transcriptome of MGE cells at a spatial resolution of 50 microns. Distinct groups of progenitor cells showing different stages of interneuron maturation were identified and topographically mapped based on their genome-wide transcriptional pattern. Although proliferating potential decreased rather abruptly outside the ventricular zone, a ventro-lateral gradient of increasing migratory capacity was identified, revealing heterogeneous cell populations within this neurogenic structure. Read the full article HERE.

Two new postdoc fellows join KI group to study roles of growth factor receptors in neuron differentiation, survival and function

Favio Krapacher obtained his PhD at the Universidad Nacional de Córdoba, Argentina, in December 2013. His thesis work focused on studies of p35 transgenic mice as a model of attention deficit hyperactivity disorder, and included a series of behavioral, pharmacological and biochemical studies. Favio joins the KI team to study the role of Alk4 signaling in controlling the differentiation and migration of specific subtypes of forebrain GABAergic interneurons.

Nuria Gresa-Arribas obtained her PhD at the Universiy of Barcelona, Spain, in 2011. Her thesis examined the neurotoxic role of pro-inflammatory microglial cells and the role of C/EBPs transcription factors. She later worked as postdoctoral fellow under the direction of Dr. Josep Dalmau at the same university for studies of autoimmune neurologic diseases associated with antibodies to neuronal cell surface or synaptic proteins. Nuria will join the KI team in November to pursue studies of p75 signaling mutant mice.

Research Assistant joins KI group to help with mouse genotyping

Petronella Johansson trained at Kristianstad Highschool and subsequently pursued doctoral studies at the Scottish Fish Immunology Research Centre, University of Aberdeen, United Kingdom, where she obtained a PhD in 2014. Petronella joins our group to help with mouse breeding and genotyping, as well as molecular techniques and admin duties.

New discovery explains how ALK7 receptor regulates fat accumulation in obesity

In our latest paper, we report that the sensitivity of fat cells to signals that increase the breakdown of fat is linked to the receptor ALK7. The discovery, which is published in eLife, suggests that ALK7 is an interesting target for future strategies to treat obesity.

The ALK7 receptor is predominantly found in fat cells and tissues involved in controlling the metabolism. Intriguingly, mice with a mutation in ALK7 accumulate less fat than mice with a functional version of the protein. Until now, it has not been known why.

We created mice whose fat cells lack ALK7, but whose other cells all produce ALK7 as normal. We found that fat cells lacking the ALK7 receptor are more sensitive to adrenaline and noradrenaline signals, a finding that can explain why they accumulate less fat even though the mice were on a high-fat diet. Adrenaline and noradrenaline are central players in metabolism. These hormones trigger the burst of energy and increase in heart rate and blood pressure that are needed for the “fight-or-flight” response. The hormones normally stimulate the breakdown of fat, but when nutrients are plentiful, fat cells become resistant to this signal and instead store fat. This mechanism evolved to facilitate energy storage during times of abundant food supply, enhancing survival upon starvation. In the industrialized world where food is constantly accessible, this resistance can cause an unhealthy increase in body fat and result in obesity.

We then investigated if it is possible to prevent obesity by blocking ALK7. At present, there are no known ALK7 inhibitors, but we solved this by generating mice with a special mutation in ALK7 which renders it sensitive to inhibition by a chemical substance. This made it possible for us to block the receptor at any time in an otherwise normal adult animal.

Using this approach, we could get these mice to be leaner on a high fat diet simply by administration of the chemical. This suggests that acute inhibition of the ALK7 receptor can prevent obesity in adult animals, says Tingqing Guo, first author of the study.

We have also showed that the ALK7 receptor works in a similar way in human fat cells as it does in mice.

Overall, these results suggest that blockade of the ALK7 receptor could represent a novel strategy to combat human obesity, says Carlos Ibanez, principal investigator of the study.

The work was supported by grants from the European Research Council, Swedish Research Council, Strategic Research Program in Diabetes of Karolinska Institutet, Swedish Cancer Society, Knut and Alice Wallenberg Foundation, the National University of Singapore and the National Medical Research Council of Singapore. eLife is a peer-reviewed open-access scientific journal established at the end of 2012 by Nobel Prize Winner Randy Schekman, with support from the Howard Hughes Medical Institute, Max Planck Society and Wellcome Trust.

The paper is freely accessible and can be found HERE.

New Call: Postdoc Fellows in Neurobiology | Metabolism

Work at Carlos Ibanez laboratory focuses on understanding the functions and signaling mechanisms of  growth factors and their receptors in neural development and injury responses and metabolic regulation, for the development of better therapies to diseases of the nervous system and metabolic disorders.

Carlos Ibanez is Professor of Neuroscience at the Karolinska Institute in Stockholm, Sweden.

Postdoctoral fellows are currently being recruited to the laboratory to advance research on growth factor receptor signaling and function in neurodevelopment and neural injury. We are seeking talented, innovative and enthusiastic researchers with a PhD awarded within the last 5 years. Candidates with expertise in i) molecular and cellular neurobiology, neurodevelopment or ii) molecular and cellular endocrinology, metabolic research and iii) mouse genetics are encouraged to apply.

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 2014.

Deadline for application is May 10, 2014

New paper reveals differential regulation of pancreatic insulin secretion by Smad proteins and activin ligands

Diabetologia has now published online our latest paper describing differential actions of activins A and B and Smad proteins 2 and 3 on the regulation of insulin secretion by pancreatic beta cells (Wu et al., 2013).

Glucose-stimulated insulin secretion (GSIS) from pancreatic beta-cells is regulated by paracrine factors whose identity and mechanisms of action are incompletely understood. Activins are expressed in pancreatic islets and have been implicated in the regulation of GSIS. Activins A and B signal through a common set of intracellular components, but it is unclear whether they display similar or distinct functions in glucose homeostasis. Glucose homeostatic responses were examined in mice lacking activin B and in pancreatic islets derived from these mutants. The ability of activins A and B to regulate downstream signalling, ATP production and GSIS in islets and in beta-cells was compared. Mice lacking activin-B displayed elevated serum insulin levels and glucose-stimulated insulin release. Injection of a soluble activin B antagonist phenocopied these changes in wild type mice. Isolated pancreatic islets from mutant mice showed enhanced GSIS which could be rescued by exogenous activin B. Activin B negatively regulated GSIS and ATP production in wild type islets, while activin-A displayed opposite effects. The downstream mediator Smad3 responded preferentially to activin B in pancreatic islets and beta-cells, while Smad2 showed preference for activin A, indicating distinct signalling effects of the two activins. In line with this, overexpression of Smad3, but not Smad2, decreased GSIS in pancreatic islets. These results reveal a tug-of-war between activin ligands in the regulation of insulin secretion by beta-cells and suggest that manipulation of activin signalling could be a useful strategy for the control of glucose homeostasis in diabetes and metabolic disease.

Read the full article HERE.

Carlos Ibanez Lab wins consecutive Advanced Grant from the European Research Council

The European Research Council (ERC) has announced that Carlos Ibanez is among the winners of the 2013 Advanced Grant competition. At 2.5 million Euros –for a 5 year project– the ERC Advanced Grant has become one of the most prestigious research awards in Europe. In this round, a total of 284 researchers were awarded from over 2,400 applicants, a success rate of 11.8%.

Two new postdoc fellows to join KI 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. Her postdoctoral work on reverse signaling by TNF ligands was recently published in Nature Neuroscience. Lilian will join the Stockholm p75 team in August 2013 to investigate the interplay between RIP2 and RhoGDI in the control of axon growth and degeneration by p75NTR and its ligands.

Diana Fernandez Suarez obtained her PhD in 2012 at the Center for Applied Medical Research University of Navarra, Pamplona, Spain, under the direction of Drs.Rafael Franco and Maria Soledad Aymerich. Her PhD thesis was dedicated to anatomical and funcitonal studies of the globus pallidus after manipulation of the endocanabinoid system in animal models of Parkinson’s disease. She performed postdoctoral work at the same laboratory during the past year. Diana will join the KI GDNF team in August 2013 to investigate adult functions of GFRa1 signaling in the healthy and diseased brain.

Open Positions: Postdoc Fellows in Neurobiology | Metabolism

Work at our laboratory focuses on understanding the functions and signaling mechanisms of neuronal growth factors in neural development, injury responses and metabolic regulation, for the development of better therapies to diseases of the nervous system and metabolism.

Postdoctoral fellows are currently being recruited to the laboratory. We are seeking talented, innovative and enthusiastic researchers with a PhD awarded within the last 10 years. Candidates with expertise in neurobiology, metabolism and mouse genetics are encouraged to apply.

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 2013.

Deadline for application is March 31, 2013.

New review explores the structure, evolution and function of the RET receptor tyrosine kinase

Cold Spring Harbour Perspectives in Biology has published Carlos Ibanez’s review on the structure and physiology of the RET receptor tyrosine kinase as part of their collection of reviews on receptor tyrosine kinases. RET, GDNF family ligands, and GFRα coreceptors activate signaling pathways involved in kidney and nervous system development. RET mutations cause Hirschsprung’s disease and at least four cancers. Read the full paper HERE.

 

New paper provides insights into the logic of neurotrophin signaling through the p75 neurotrophin receptor

Cell Reports publishes today our latest paper describing a structure-function map of the death domain of the p75 neurotrophin receptor (Charalampopoulos et al. 2012)

Structural determinants underlying signaling specificity in the tumor necrosis factor receptor superfamily (TNFRSF) are poorly characterized and it is unclear whether different signaling outputs can be genetically dissociated. The p75 neurotrophin receptor (p75NTR), also known as TNFRSF16, is a key regulator of trophic and injury responses in the nervous system. In this paper, we describe a genetic approach to dissect p75NTR signaling and decipher its underlying logic. Structural determinants important for regulation of cell death, NF-kB and RhoA pathways were identified in the p75NTR death domain. Pro-apoptotic and pro-survival pathways mapped onto non-overlapping epitopes, demonstrating that different signaling outputs can be genetically separated in p75NTR. Dissociation of JNK and caspase-3 activities indicated that JNK is necessary but not sufficient for p75NTR-mediated cell death. RIP2 recruitment and RhoGDI release were mechanistically linked, indicating that competition for DD binding underlies cross-talk between NF-kB and RhoA pathways in p75NTR signaling. These results provide new insights into the logic of p75NTR signaling and pave the way for a genetic dissection of p75NTR function and physiology.

Read the full paper HERE.

Carlos Ibanez appointed as Wallenberg Scholar

The Knut and Alice Wallenberg Foundation has today appointed Carlos Ibanez as a Wallenberg Scholar. The award includes a research grant of 15 million Swedish crowns over 5 years. Quote from the Foundation’s website: “The Foundation’s purpose is to support Swedish research and thereby strengthen Sweden as a research nation. Since 2009, we have appointed a total of 46 Wallenberg Scholars. The appointed researchers all belong to the international research forefornt in all areas of science, with an emphasis on medicine and the natural sciences, says Peter Wallenberg Jr., vice chairman of the Knut and Alice Wallenberg Foundation.” Read the text of the announcement (in Swedish) HERE and press release from Karolinska Institute HERE.

New paper reveals critical role of GFRa1 signaling in the development and function of the main olfactory system

The Journal of Neuroscience publishes today our paper on the role of the GDNF receptor GFRa1 in the main olfactory system (Marks et al. 2012). In this work, we investigated the consequences of GFRα1 deficiency for mouse olfactory system development and function.

GDNF and its receptor GFRα1 are prominently expressed in the olfactory epithelium (OE) and olfactory bulb (OB), but their importance for olfactory system development has been unknown. In the OE, we found that GFRα1 was expressed in basal precursors, immature olfactory sensory neurons (OSNs), and olfactory ensheathing cells (OECs), but was excluded from mature OSNs. The OE of newborn Gfra1 knock-out mice was thinner and contained fewer OSNs, but more dividing precursors, suggesting deficient neurogenesis. Immature OSN axon bundles were enlarged and associated OECs increased, indicating impaired migration of OECs and OSN axons. In the OB, GFRα1 was expressed in immature OSN axons and OECs of the nerve layer, as well as mitral and tufted cells, but was excluded from GABAergic interneurons. In newborn knock-outs, the nerve layer was dramatically reduced, exhibiting fewer axons and OECs. Bulbs were smaller and presented fewer and disorganized glomeruli and a significant reduction in mitral cells. Numbers of tyrosine hydroxylase-, calbindin-, and calretinin-expressing interneurons were also reduced in newborn mice lacking Gfra1. At birth, the OE and OB of Gdnf knock-out mice displayed comparable phenotypes. Similar deficits were also found in adult heterozygous Gfra1+/− mutants, which in addition displayed diminished responses in behavioral tests of olfactory function. We conclude that GFRα1 is critical for the development and function of the main olfactory system, contributing to the development and allocation of all major classes of neurons and glial cells.

Read the full paper HERE.

Thesis nailing


PhD student Carolyn Marks nailed her thesis at the KI library this week. Tradition obliges, and the golden nail went into the wooden slab one more time.

The event marks the final count-down for her thesis defense, to take place on December 7. Attracted by the prospect of champagne and refreshments, fellow lab mates joined in for the occassion.

Photograph by postdoc fellow Tingqing Guo.

Carlos Ibanez starts new laboratory at the Life Sciences Institute of the National University of Singapore

Starting in the Fall of 2012, a new laboratory dedicated to neurotrophic factor research will be established at the Life Sciences Institute (Neurobiology Programme) of the National University of Singapore. The research actitivies of the NUS lab will run in parallel to and complement with those ongoing at the KI lab. The initial focus of the NUS group will be on genetic studies of death receptor signaling and physiology, as well as the identification of novel, mechanism-based receptor inhibitors. Follow developments in the NUS lab at carlosibanezlab.se/NUS.

PhD student Carolyn Marks to defend doctoral thesis in December

PhD student Carolyn Marks is set to defend her thesis, entitled “Regulatory mechanisms in olfactory system assembly and function”, on December 7, 2012. Her external examiner will be Professor Charles Greer from Yale University. Faculty members in the thesis committee will be Professors Ole Kiehn (KI), Jonas Muhr (KI), Tibor Harkany (KI) and Anders Lansner (KTH). Watch this space for updates on thesis nailing and other rituals.

New paper reveals role of activin receptor ALK7 in female reproduction

The FASEB Journal has published our paper on the role of the activin receptor ALK7 in the control of female reproduction (Sandoval-Guzman et al. 2012). In this work, we investigated the expression and function of the activin receptor ALK7 in the female reproductive axis using Alk7-knockout mice.

Alk7-knockout females showed delayed onset of puberty and abnormal estrous cyclicity, had abnormal diestrous levels of FSH and LH in serum, and their ovaries showed premature depletion of follicles, oocyte degeneration, and impaired responses to exogenous gonadotropins. In the arcuate nucleus, mutant mice showed reduced expression of Npy mRNA and lower numbers of Npy-expressing neurons than wild- type controls. Alk7 knockouts showed a selective loss of arcuate NPY/AgRP innervation in the medial preoptic area, a key central regulator of reproduction. These results indicate that ALK7 is an important regulator of female reproductive function and reveal a new role for activin signaling in the control of hypothalamic gene expression and wiring. Alk7 gene variants may contribute to female reproductive disorders in humans, such as polycystic ovary syndrome.

Read the full paper HERE.

New postdoc fellow to join metabolism team for islet biology work with Alk7 and Alk4 mutant mice

Karima Mezghenna obtained a PhD in Biology and Health Sciences at Montpellier 1 University under the direction of Prof. Anne-Dominique Lajoix with the title “Role of pancreatic and muscular neuronal NO synthases in the pathogenesis of prediabetic states”. Her work focused on unraveling compensatory mechanisms involved in insulin hypersecretion in insulin resistant rats with a special interest in the nitric oxide pathway. Karima will be joining our metabolism team in October to study the role of activin signaling through Alk7 and Alk4 in islet biology and the control of glucose homeostasis.

Upcoming event: grand finale of Molpark EU network on the island of Ischia

September 7-10 will see Carlos Ibanez and lab members Claire Kelly, Maritina Sergaki, Sabrina Zechel and Carolyn Marks heading to the island of Ischia, off the coast of Naples, for the Vth and final meeting of the Molpark EU network. A fitting venue to close a very exciting scientific partnership which we hope will continue in the future.

Molparkers meet at 4th EU network conference in Santorini: photographs

The Molpark crew met on the island of Santorini in the Aegean sea on October 30 to November 2, 2011, for the IVth Molpark network conference. Magnificent seascapes greeted the Molparkers as they locked themselves up to discuss the latest scientific advancements made by the different teams. Watch what they did when they were not talking science by visitng the photo gallery.

New review on p75NTR signaling in nervous system injury out in Trends in Neurosciences

Our review on p75 neurotrophin signaling in nervous system injury has been made available as a paper in press in the Trends In Neurosciences web site.

Injury or insult to the adult nervous system often results in reactivation of signaling pathways that are normally only active during development. The p75 neurotrophin receptor (p75NTR) is one such signaling molecule whose expression increases markedly following neural injury in many of the same cell types that express p75NTR during development. A series of studies during the past decade has demonstrated that p75NTR signaling contributes to neuronal and glial cell damage, axonal degeneration and dysfunction during injury and cellular stress. Why the nervous system reacts to injury by inducing a molecule that aids the demise of cells and axons is a biological paradox that remains to be explained satisfactorily. On the other hand, it may offer unique therapeutic opportunities for limiting the severity of nervous system injury and disease.

Read the full paper HERE.

 

Postdoc position in pancreatic islet biology

A postdoctoral position is available for experienced molecular endocrinologists to join our team investigating the role of growth factor signaling in metabolic regulation using mouse models carrying mutations in the Activin receptors ALK7 and ALK4, novel regulators of glucose homeostasis and energy balance (see Bertolino et al. and Andersson et al., PNAS 2008). The aim of the project is to understand the functional role of activin signaling through ALK7 and ALK4 in pancreatic islets and its contribution to the regulation of insulin secretion and glucose homeostasis. In order to tackle these questions, we have recently generated conditional and chemically inducible mutant mouse lines which will be available for analysis at the start of the project.

We are seeking a talented, innovative and enthusiastic researcher with a PhD awarded within the last 4 years. Highly motivated candidates with a genuine interest in metabolic regulation and mouse genetics are encouraged to apply. Priority will be given to candidates with strong expertise in pancreatic islet biology and studies of insulin secretion and glucose homeostasis.

Applications, including CV, list of publications and statement of future interests should be sent to . Applicants should arrange to have at least two confidential letters of reference to be sent directly by referees.

Funding is available for an initial period of 2 years, starting any time during 2012.

Review of applications will begin immediately and will continue until the position is filled.

Lab retreat December 15-16 at Sigtuna Stiftelsen

Our group will be heading to the charming old town of Sigtuna for a 2-day lab retreat on December 15-16. We will be hosted by the Sigtuna Stiftelsen, originally founded as a forum for spiritual development, today functioning as a conference center. From its statutes, it can be read that “the Sigtuna Foundation, which begins its actual operations in 1917, has as its mission to support and prepare a home for volunteer work for the Lutheran faith and religious education in our country”. We will see about that. Our plan is to have each member of our group making a presentation on a free topic, with a connection to science. And there will be a hike and picnic in the forest, weather permitting. We are looking forward to an exciting and stimulating couple of days. Watch this space for more.

Heading to Santorini for the IVth meeting of the Molpark network

This weekend, Miriam Schiff and Carlos Ibanez will be on their way to the island of Santorini in the southern Aegean Sea for the IVth meeting of the Molpark EU network. We are hoping the Greek strikers will let us getting in and out without much hassle. Watch this space for more, and look HERE for other Molpark events and announcements.

New JCS paper reveals connection between MET and GDNF signaling in GABAergic interneuron development

The Journal of Cell Science publishes today our paper on the interaction between MET and GDNF signaling in the control of cortical GABAergic interneuron development (Perrinjaquet et al. 2011). This work demonstrates that responsiveness to GDNF in Gfra1 knock-out GABAergic interneurons can be restored upon addition of soluble GFRa1. As these neurons express neither RET nor NCAM, this result is only compatible with the existence of a novel transmembrane receptor partner for the GDNF-GFRa1 complex in GABAergic interneurons. Neither ErbB4 nor MET were found to fullfil this role. Unexpectedly, however, inhibition of MET (or its ligand HGF) per se promoted neuronal differentiation and migration and enhanced the activity of GDNF on GABAergic neurons. In agreement with this, Met mutant neurons showed enhanced responsiveness to GDNF and elevated levels of GFRa1 expression, both in vitro and in vivo. These results demonstrate the existence of a novel transmembrane receptor partner for the GDNF––GFRa1 complex and uncover an unexpected interplay between GDNF––GFRa1 and HGF––MET signaling in the early diversification of cortical GABAergic interneuron subtypes. Read the full paper HERE.

New postdoc fellow to join p75 team for in vivo work with mutant mice

Claire Kelly obtained her PhD earlier this year at the MRC Clinical Sciences Centre, Imperial College London, UK. Her work, conducted under the direction of Dr. Vasso Episkopou, focused on the role of the E3 ubiquitin ligase Arkadia2C in motor neuron development in the mouse. Claire will be joining our p75 team in October to study the phenotypes of p75 mutant mice.

 

Photographs from Neurotrophic Factors GRC 2011 now available

Photographs taken during the GRC 2011 conference are now available for viewing at the Conferences Photo Gallery HERE. Watch speakers, discussion leaders and other participants enjoy 5 days of cutting edge science among cliff walks and seafood delicacies at the beautiful setting of Newport in the Rhode Island coast.

Gordon Research Conference on Neurotrophic Factors chaired by Carlos Ibanez to kick-off in Newport, Rhode Island, June 5

The 10th edition of the Gordon Research Conference (GRC) devoted to Neurotrophic Factors will take place at Salve Regina University in Newport, Rhode Island, June 5-10, 2011. Carlos Ibanez, who was vice-chair in 2009, will chair the 2011 conference alongisde Rosalind Segal from Harvard University as vice-chair. This GRC is the most important forum showcasing cuting-edge developments in neurotrophic factor research. The 2011 edition will gather a mix of new and old comers and cover all aspects of neurotrophic factor research, from structure and signal transduction to functions in development, neuronal plasticity and disease. For program information and registration visit the conference website HERE. Registration closes May 8, 2011.

Science, Northern Lights meet at 3rd Molpark network conference in Finland

The third meeting of EU FP7 Molpark network took place on March 27-29, 2011, at Saariselka, 250km above the arctic circle in the Finnish Lapland. Excellent science met with white untouched snow from the Urho Kekkonen National Park, Northern Lights and a selection of Lapland food delicacies. Follow the adventures of the Molpark crew in this remote corner of the planet by visiting the photo gallery.

Imminent arrival of new laser confocal microscope

It is the Zeiss LSM700 with four solid-state lasers mounted on an AxioImager Z2 stand. There is big excitment in the lab and we all hope that this will significantly improve the workflow of our microscopy work. The proof of the pudding…

Upcoming event: Molpark network meets in the Finnish Lapland

The third meeting of the FP7 EU network Molpark will take place during March 27-30 at Saariselka in the Finnish Lapland, 250 km above the arctic circle. We will be heading over for some good science and the hope to see the Northern Lights. Watch this space for more, and look HERE for other Molpark events and announcements.

Lab Xmas Dinner 2010 documented for posterity

This year, our lab Xmas dinner took place at a Greek restaurant, to the acclaim of Greek and non-Greek lab members alike. Secret Santa was particularly generous this time. And some sipporo helped loosen up the dancers. Who could they have been? Find out HERE.

Sabbatical in Singapore

Carlos Ibanez and Annalena Moliner are heading to Singapore on December 18 for a 5-month sabbatical until May 2011. They will be hosted by Dr. Bing Lim of the Genome Institute of Singapore and Dr. Sai Kiang Lim of the Institute of Medical Biology, located at the Biopolis campus run by the Agency for Science, Technology and Research (A*STAR), Singapore’s lead government agency dedicated to fostering world-class scientific research. They will be working on several of our ongoing collaborative projects with these groups, applying advanced functional genomics and stem cell biology methods to study pancreatic islet development and function in cells and tissue derived from mouse mutants generated at the laboratory.

Thesis nailing


PhD student Maurice Parrinjaquet nailed his thesis at the KI library. Traditional hammer in hand, Maurice hammered the golden nail on the wooden slab from which all recent theses of the institute hang unassumingly.

The emotive event marked the start of the final count-down for his thesis defense, to take place on December 16. Attracted by the prospect of champagne and refreshments, fellow lab mates joined in for the occassion.

Photograph by postdoc fellow Tingqing Guo.

New lab technician joins forces to help us with mice, genotyping

Annika Andersson studied cell and molecular biology at Sodertorn Highschool. She did her exam project at Karolinska Institutet. She has worked as lab technician at AstraZeneca R&D, Sodertalje, since 2002.

PhD student Maurice Perrinjaquet to defend his thesis in December

PhD student Maurice Perrinjaquet is set to defend his thesis, entitled “Control of neuronal survival, migration and outgrowth by GDNF and its receptors”, on December 16, 2010. His external examiner will be Professor Rosalind Segal from Harvard Medical School. Faculty members of his thesis committee will be Professors Piergiorgio Percipalle (KI), Ulf Eriksson (KI) and Finn Hallbook (Uppsala University). Watch this space for more information.

New postdoc fellow to join our metabolism team in 2011

Patricia Marmol obtained her PhD in November 2009 at the Department of Molecular Biology (Centro de Biologia Molecular Severo Ochoa) of the Universidad Autonoma de Madrid. During her thesis, Patricia studied the role of the mitochondrial aspartate-glutamate carrier (AGC1/Aralar/SLC25A12), the key member of the malate-aspartate shuttle, in glucose metabolism in the INS-1 beta cell line and in transgenic AGC1 mutant mice.

ENDOCYTE network comes to an end at Halkidiki

The closure meeting of the ENDOCYTE Research and Training Network sponsored by EU’s FP6 took place at Porto Carras, Halkidiki, Greece, on August 22-25, 2010. In addition to presentations by selected fellows and PIs from the Endocyte network, an outstanding group of invited guest speakers included Casper Hoogenraad, Marta Miaczynska, Blagoy Blagoev, Leif Dehmelt, Eleanor Coffey, Carsten Schultz and former lab fellow Ioannis Charalampopoulos. A selection of photographs taken during the meeting is now available. Check out the Photo Galleries link in the left for more Endocyte photographs. For access to the Endocyte web site click HERE.

Two new postdoc fellows to join GDNF team in the Fall

Maritina Sergaki obtained a PhD in molecular and cellular neurobiology in June 2009 at the Laboratory of Cellular and Molecular Neurobiology of the Hellenic Pasteur Institute in Athens, Greece, under the direction of Prof. Rebecca Matsas. During her PhD, Maritina generated and characterized a mouse mutant for the neuronal protein BM88, also called Cend1. She discovered morphological abnormalities in the cerebellum of the mutants as well as motor deficits. Since her PhD, Maritina has worked as a postdoctoral fellow at the Biomedical Research Foundation of the Academy of Athens under the direction of Prof. Irini Skaliora. Her project aimed at elucidating differential roles of ERK1 and ERK2 kinases in synaptic plasticity.

Miriam Schiff completed her PhD thesis in neuroscience in April 2010 at the Dept. of Cellular Chemistry, Hannover Medical School, Germany, under the direction of Prof. Herbert Hildebrandt. During her thesis, entitled “Development of the dopaminergic system and the reticular thalamic nucleus in polysialic acid-deficient mice“, Miriam investigated the development of midbrain dopaminergic neurons and the formation of thalamocortical and corticothalamic projections as well as the reticular thalamic nucleus in a mutant mouse lacking the two known polysialic acid synthases STX and PST.

New paper linking SHP2 phosphatase to RET signaling out in the JBC

Our latest paper has been made available today at the Papers In Press site of the Journal of Biological Chemistry (Perrinjaquet et al. JBC 2010). This work identifies the protein tyrosine phosphatase SHP2 as a novel direct interactor of the receptor tyrosine kinase RET. SHP2 is the first effector known to bind to phosphorylated Tyr687 in the juxtamembrane region of the receptor. SHP2 recruitment contributes to the ability of RET to activate the PI3K/AKT pathway and promote survival and neurite outgrowth in primary neurons. Together with other findings, this work establishes SHP2 as a novel positive regulator of the neurotrophic activities of RET, and reveal Tyr687 as a critical platform for integration of RET signals. We anticipate that several other phospho-tyrosines of unknown function in neuronal receptor tyrosine kinases will also support similar regulatory functions. Read the full paper HERE.

Second example of ligand-induced cell adhesion discovered

Ligand-induced cell adhesion was discovered at our laboratory as one of the mechanisms underlying the synaptogenic effects of GDNF and its receptor GFRa1 (Ledda et al. Nat. Neurosci. 2007). GDNF treatment of cells expressing GFRa1 induces the formation of cell aggregates in a saturable process that requires continuous presence of GFRa1 on the cell membrane. Due to the presence of GFRa1 in pre- and post-synaptic specializations, and its requirement for synapse formation in vitro and in vivo, this novel cell adhesion activity may contribute to synapse formation and neuronal connectivity. Although the precise molecular mechanism (whether trans-homodimerization, receptor allosterism, or other) is still unclear, it represented the first example of cell adhesion mediated by binding of a ligand to a cell surface receptor which otherwise lacks cell adhesion activity. Now a group of researchers led by Prof. Masayoshi Mishina from the Uiversity of Tokyo have discovered a second example of this phenomenon, suggesting that it may be a general mechanism of cell-cell engagement. The new work involves the synaptogenic actions of GluRd2 and Neurexin receptors in cooperation with the Cerebellin 1 (Cbln1) ligand and has been published in the June 11 issue of Cell.

Photographs of Molpark meeting in Amalfi coast finally here

“Den som vantar pa nagot gott …” Indeed, a selection of the photographs taken during our last Molpark meeting is -finally- seeing the light of day. Follow the wanderings of the Molpark crew through the wastelands of Seiano, Pompei and Positano amid awful landscapes and horrid foods in some of the worst weather conditions imaginable.

Postdoc position: GDNF signaling in GABAergic interneuron differentiation and migration

A postdoctoral position is available for experienced neurobiologists to join our team investigating the role of GDNF and its receptors in the control of cortical interneuron development and function (see Pozas et al. Neuron 2005 and Canty et al. J. Neurosci. 2009). The aim of this research is to elucidate novel pathways regulating the diversification, migration and allocation of cortical inhibitory interneurons. In order to tackle these questions, we have at our disposition a battery of conditional and inducible mutant mouse lines which will be available for analysis at the start of the project.

We are seeking a talented, innovative and enthusiastic researcher with a PhD awarded within the last 4 years. Highly motivated candidates with a genuine interest in developmental neuroscience, signal transduction and mouse genetics are encouraged to apply. Priority will be given to candidates with strong expertise in one or more of the following areas: mouse forebrain development, cell transplantation, birth dating and lineage analyses, neuron primary culture, cell signaling assays and cell microscopy.

Visit the lab Open Positions page for details on how to apply.

New postdoc fellow to join ALK7 team

With a PhD from the Shanghai Institute of Biochemistry and Cell biology and a successful postdoc tenure at the lab of Alexandra McPherron at NIDDK, NIH, Tingqing Guo will be joining our group after the summer. His work at the McPherron lab focused on the role of myostatin in insulin sensitivity and fat deposition.

KI 200 anniversary review out in BBRC

Honoring the 200 anniversary of the Karolinska Institute, Biochemical and Biophysical Research Communications (BBRC) has published a special issue with a series of mini-reviews from KI scientists illustrating recent developments within some areas of biomedical research at the molecular level that have been actively pursued at KI. Our contribution, entitled “Beyond the cell surface: New mechanisms of receptor function“, discusses novel aspects of receptor signaling based on some of our recent investigations of the GDNF/GFRa1 signaling system.

Former postdoc fellow Svend Kjaer gets first glimpse at the structure of the Ret ECD

After quite some perseverance and few years of work, the 3D structure of the N-terminal portion of the extracellular domain (ECD) of the RET receptor has been determined by former postdoc fellow Svend Kjaer working at the lab of Nel McDonald in CRUK, London. The paper has appeared online in Nature Structure and Molecular Biology. During his tenure at our lab in 1998-2004, Svend studied RET intensively and published several papers on its biosynthesis, oligomerization and structure-function relationships. He spent several years producing fragments of the RET extracellular domain for structural characterization. Although sufficient for biochemical analyses, the yield was never enough for crystallization. The breakthrough at CRUK came after introduction of a few mutations, including two that knocked-off a couple of unpaired cysteines. The new structure gives tantalizing insights into how RET interacts with the GDNF ligand and co-receptor GFRa1 and how its mutation causes disease.

Upcoming event: ENDOCYTE kick-out conference in Porto Carras, Greece

The ENDOCYTE Research and Training network finishes off with a mini-conference in Porto Carras, Northern Greece, on August 22-25, organized by postdoc fellow Anastasia Simi. The preliminary program includes talks from Philippe Bastiaens, Isabel Guerrero, Ivan Dikic, Harald Stenmark, Anastasia Simi, Ioannis Charalampopoulos, Casper Hoogenraad, Marta Miaczynska, Blagoy Blagoev, Leif Dehmelt, Eleanor Coffey, Carsten Schultz and fellows from the ENDOCYTE network. More to come!

New lab member on its way

Annalisa Vicario is to join our group on May 2010. Annalisa defended her thesis in the group of Enrico Tongiorgi at University of Trieste, Italy. Her thesis work was on mechanisms controlling BDNF mRNA localization and regulation of protein expression. She will join our p75ntr team as a postdoc fellow. We look forward to have her in our group.

Open positions: deadline coming close...

At the end of this month, the first deadline for postdoc position in several projects at our lab is closing. Visit the Open Positions page for more details.

Upcoming event: Molpark meeting in the Amalfi coast

A few of us are heading this weekend to the Amalfi coast for the second meeting of the Molpark network. If the Molpark kick-off meeting of last year in Izmir, Turkey may serve as an indication, this promises to be a memorable event. We are crossing our fingers hoping that the volcano in Island will not ruin our plans. Watch this space!