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!
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.