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Genome-wide studies have identified three missense variants in the human gene ACVR1C, encoding the TGF-β superfamily receptor ALK7, that correlate with altered waist-to-hip ratio adjusted for body mass index (WHR/BMI), a measure of body fat distribution.
In our latest paper, to move from correlation to causation and understand the effects of these variants on fat accumulation and adipose tissue function, we introduced each of the variants in the mouse Acvr1c locus and investigated metabolic phenotypes in comparison with a null mutation.
Mice carrying the I195T variant showed resistance to high fat diet (HFD)-induced obesity, increased catecholamine-induced adipose tissue lipolysis and impaired ALK7 signaling, phenocopying the null mutants. Mice with the I482V variant displayed an intermediate phenotype, with partial resistance to HFD-induced obesity, reduction in subcutaneous, but not visceral, fat mass, decreased systemic lipolysis and reduced ALK7 signaling. Surprisingly, mice carrying the N150H variant were metabolically indistinguishable from wild type under HFD, although ALK7 signaling was reduced at low ligand concentrations.
Together, these results validate ALK7 as an attractive drug target in human obesity and suggest a lower threshold for ALK7 function in humans compared to mice.
The paper has been published in Molecular Metabolism
How receptors juggle their interactions with multiple downstream effectors remains poorly understood.
In our latest paper, we report that the outcome of death receptor p75NTR signaling is determined through competition of effectors for interaction with its intracellular domain, in turn dictated by the nature of the ligand. While NGF induces release of RhoGDI through recruitment of RIP2, thus decreasing RhoA activity in favor of NFkB signaling, MAG induces PKC-mediated phosphorylation of the RhoGDI N-terminus, promoting its interaction with the juxtamembrane domain of p75NTR, disengaging RIP2, and enhancing RhoA activity in detriment of NF-kB. This results in stunted neurite outgrowth and apoptosis in cerebellar granule neurons. If presented simultaneously, MAG prevails over NGF. The NMR solution structure of the complex between the RhoGDI N-terminus and p75NTR juxtamembrane domain reveals previously unknown structures of these proteins and clarifies the mechanism of p75NTR activation.
These results show how ligand-directed competition between RIP2 and RhoGDI for p75NTR engagement determine axon growth and neuron survival. Similar principles are likely at work in other receptors engaging multiple effectors and signaling pathways.
The paper has been published in EMBO Reports
Adipocyte hyperplasia and hypertrophy are the two main processes contributing to adipose tissue expansion, yet the mechanisms that regulate and balance their involvement in obesity are incompletely understood. Activin B/GDF-3 receptor ALK7 is expressed in mature adipocytes and promotes adipocyte hypertrophy upon nutrient overload by suppressing adrenergic signaling and lipolysis. In contrast, the role of ALK4, the canonical pan-activin receptor, in adipose tissue is unknown.
In our latest paper, we report that, unlike ALK7, ALK4 is preferentially expressed in adipocyte precursors, where it suppresses differentiation, allowing proliferation and adipose tissue expansion. ALK4 expression in adipose tissue increases upon nutrient overload and positively correlates with fat depot mass and body weight, suggesting a role in adipose tissue hyperplasia during obesity. Mechanistically, ALK4 signaling suppresses expression of CEBPα and PPARγ, two master regulators of adipocyte differentiation. Conversely, ALK4 deletion enhances CEBPα/PPARγ expression and induces premature adipocyte differentiation, which can be rescued by CEBPα knockdown.
These results clarify the function of ALK4 in adipose tissue and highlight the contrasting roles of the two activin receptors in the regulation of adipocyte hyperplasia and hypertrophy during obesity.
The paper has been published in The Journal Of Biological Chemistry
ΔfosB is an alternatively spliced product of the FosB gene that is essential for dopamine-induced reward pathways and that acts as a master switch for addiction. However, the molecular mechanisms of its generation and regulation by dopamine signaling are unknown.
In this new paper, we report that dopamine D1 receptor signaling synergizes with the activin/ALK4/Smad3 pathway to potentiate the generation of ΔFosB mRNA in medium spiny neurons (MSNs) of the nucleus accumbens (NAc) via activation of the RNA-binding protein PCBP1, a regulator of mRNA splicing. Concurrent activation of PCBP1 and Smad3 by D1 and ALK4 signaling induced their interaction, nuclear translocation, and binding to sequences in exon-4 and intron-4 of FosB mRNA. Ablation of either ALK4 or PCBP1 in MSNs impaired ΔFosB mRNA induction and nuclear translocation of ΔFosB protein in response to repeated co-stimulation of D1 and ALK4 receptors. Finally, ALK4 is required in NAc MSNs of adult mice for behavioral sensitization to cocaine.
These findings uncover an unexpected mechanism for ΔFosB generation and drug-induced sensitization through convergent dopamine and ALK4 signaling.
The paper has been published in The EMBO Journal
The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown.
In this study, we used spatiotemporally controlled Cre-mediated recombination in adult mice, and found that the glial cell–derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septo-habenular and habenulo-interpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb.
These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septo-habenulo-interpeduncular pathway and attuning of anxiety and fear behaviors.
The paper has been published in PLOS Biology
Life- style change and anti-inflammatory interventions have only transient effects in obesity. It is not clear how benefits obtained by these treatments can be maintained longer term, especially during sustained high caloric intake. Constitutive ablation of the activin receptor ALK7 in adipose tissue enhances catecholamine signaling and lipolysis in adipocytes, and protects mice from diet-induced obesity.
In this study, we investigated the consequences of conditional ALK7 ablation in adipocytes of adult mice with pre- existing obesity. Although ALK7 deletion had little effect on its own, it synergized strongly with a transient switch to low- fat diet (life-style change) or anti-inflammatory treatment (Na-salicylate), resulting in enhanced lipolysis, increased energy expenditure, and reduced adipose tissue mass and body weight gain, even under sustained high caloric intake. By themselves, diet- switch and salicylate had only a temporary effect on weight gain. Mechanistically, combination of ALK7 ablation with either treatment strongly enhanced the levels of β3-AR, the main adrenergic receptor for catecholamine stimulation of lipolysis, and C/EBPα, an upstream regulator of β3-AR expression. These results suggest that inhibition of ALK7 can be combined with simple interventions to produce longer- lasting benefits in obesity.
The paper has been published in The FASEB Journal.
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.
Alvaro Carrier Ruiz received a PhD from the Faculty of Medicine of the University of Tokyo, specializing in Neurophysiology, under the supervision of Professor Masanobu Kano. Originally from Brazil, Alvaro joins our KI team to pursue studies on the physiological relevance of ALK4 signaling for brain function.
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.
Nyantakyi Samuel Agyei obtained a PhD at the Department of Pharmacy of the National University of Singapore, which focused on identifying novel small molecules selectively targeting the cell membrane of Mycobacterium tuberculosis. Samuel’s core expertise is in multi-step syntheses of small molecules, analyses of structure-activity relationships to improve compound quality, and building and managing compound libraries.
Samuel joins our KI team to develop medicinal chemistry approaches to modify and improve on candidate small molecules capable of modulating the activities of various receptors, including our recently discovered compounds targeting p75NTR, based on our article in Cell Chemical Biology.
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.
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.
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.
UPDATE : the position has been filled.
We are seeking a talented and enthusiastic researcher with expertise in medicinal chemistry and chemical biology to advance drug discovery efforts and investigations on death receptor signaling and physiology in cancer and neuronal cells. The research entails medicinal chemistry studies on small molecules targeting the p75NTR death receptor identified in our ongoing screens, with the objective to improve the pharmacokinetic and biological properties of chemical leads. Please see Goh et al. (2018) Cell Chemical Biology 25, 1485–1494 for a representative publication of this work.
Candidates will be accepted at the postdoctoral level with a PhD awarded within the last 3 years. Strong and documented expertise in medicinal chemistry and chemical biology is a requirement for consideration. The successful candidate is expected to be sufficiently independent to formulate questions, design experiments and perform research. Excellent command of the English language is reuqired.
Applications, including CV (no diploma copies needed at this time please), list of publications and statement of research interests should be sent by email to Prof. Carlos Ibanez ( ) and through the job web page of Karolinska Institute. 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.
Deadline for application is 29 September 2019.
UPDATE September 2019: The position has 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 3 years. Strong and documented expertise in molecular, cellular and histological methods of analysis as applied to studies of mouse models in the area of neuroscience is an absolute requirement for consideration. Successful applicants shall be well versed in mouse brain neuroanatomy and physiology. Expertise in analysis of mouse behavior will be an additional advantage. 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 through the job web page of Karolinska Institute: Applicants should arrange to have at least two confidential letters of reference sent independently by referees to that email address.
Deadline for application is 15 September 2019.
Michael Saleeb obtained a PhD in Organic Chemistry at Umeå University in Sweden in September 2018, under the direction of Prof. Mikael Elofsson. His PhD thesis was focused on the identification of novel antibacterial compounds against Chlamydia trachomatis & Pseudomonas aeruginosa infections. During his PhD, Michael developed expertise in chemical synthesis including C-C and C-X metal-catalyzed cross coupling, C-H insertion reactions, various heterocyclic and polyphenol syntheses. Michael joins our KI team to develop medicinal chemistry approaches to modify and improve on candidate small molecules capable of modulating the activities of various receptors, including our recently discovered compounds targeting p75NTR, based on our article in Cell Chemical Biology.
Qiang Zhang obtained his PhD at the Karolinska Institute in 2018, under the direction of Prof. Klas Wiman. His PhD thesis was entitled “Understanding p53 structure and targeting mutant p53 for improved cancer therapy”. Qiang joins our KI team to work on the identification of small molecules capable of modulating the activities of the p75 neurotrophic receptor p75NTR, based on the platform described in our recent article in Cell Chemical Biology.
Carlos Ibanez’s team returns to the Department of Neuroscience after 21 months under the administration of CMB. We are happy to be back, and hope to relocate to new space within Biomedicum later in the year.
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.
Ana Osorio Oliveira obtained her PhD at the Gladstone Institute, University of California San Francisco , USA, in 2015, under the direction of Profs. Paul Muchowski and Steven Finkbeiner. She performed postdoctoral studies at Stanford University under the direction of Dr. Xinnan Wang. Ana joins our KI team to work on studies of neurotrophic factor signaling and function in the adult nervous system.
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.
Cancerfonden, the largest research funding charity organization in Sweden, today decided to award a special grant to Carlos Ibanez lab for drug discovery efforts targeting the p75 neurotrophin receptor in melanoma and glioma, based on our pilot study recently published in Cell Chemical Biology.
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 p75NTR that induced profound conformational changes and receptor activity. The compound triggered apoptotic cell death dependent on p75NTR 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.
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.
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.
Today is the big day. After many years of planning and construction, all the preclinical departments of Karolinska Institute move into a huge, brand-new building called BIOMEDICUM. Very handsome on the inside, less so on the outside. We are just hoping for a smooth transition.
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.
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.
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.
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.
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.
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.
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.
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.
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)
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!
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.
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.
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.
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
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.
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.
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!
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.
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.
Left: Annika, Sabrina, Maritina, Karima, Nuria, Favio
Right: Lilian, Christina, Diana, Patricia, Petronella, Claire
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.
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.
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.
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.
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
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.
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%.
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.
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.
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.
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.
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.
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.
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.
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 activities 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 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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 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.
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.
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.
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…
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.
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.
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.
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.
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 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.
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.
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.
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.
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.
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.
“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.
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.
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.
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.
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.
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!
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.
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.
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!
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