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Convergent dopamine & ALK4 signaling onto PCBP1 regulates FosB splicing


New paper reveals role of activin receptor ALK7 in female reproduction

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

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

Read the full paper HERE.

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

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

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

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

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

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

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

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

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

Read the full paper HERE.


Postdoc position in pancreatic islet biology

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

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

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

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

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

Lab retreat December 15-16 at Sigtuna Stiftelsen

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

Heading to Santorini for the IVth meeting of the Molpark network

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

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

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

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

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


Photographs from Neurotrophic Factors GRC 2011 now available

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

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

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

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

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

Imminent arrival of new laser confocal microscope

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

Upcoming event: Molpark network meets in the Finnish Lapland

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

Lab Xmas Dinner 2010 documented for posterity

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

Sabbatical in Singapore

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

Thesis nailing

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

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

Photograph by postdoc fellow Tingqing Guo.

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

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

PhD student Maurice Perrinjaquet to defend his thesis in December

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

New postdoc fellow to join our metabolism team in 2011

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

ENDOCYTE network comes to an end at Halkidiki

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

Two new postdoc fellows to join GDNF team in the Fall

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

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

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

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

Second example of ligand-induced cell adhesion discovered

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

Photographs of Molpark meeting in Amalfi coast finally here

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

Postdoc position: GDNF signaling in GABAergic interneuron differentiation and migration

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

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

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

New postdoc fellow to join ALK7 team

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

KI 200 anniversary review out in BBRC

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

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

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