Group name: Cellular Neurobiology
Group leader: Åsa Fex Svenningsen
Group members:
Lektor: Åsa Fex Svenningsen PhD
Simone Hjæresen PhD
Solveig Beck Nielsen PhD
Helle Vinsløv Jensen, laborant
Department & University/Hospital/Other: Department of Molecular Medicine-Neurobiology Research. University of Southern Denmark, 5000 Odense
Funding sources: Jascha Fonden, Lægevidenskabens fremme, Johansens og Hustrus mindelegat, Oda og Hans Svenningsens fond
Description of research:
The work focuses on neuron glia communication, and the molecules used by the different cells to understand each other when differentiating and growing. We investigate this mostly in vitro, in different types of cell culture, but also in vivo using a model for de and regeneration (the cuprizone model).
A few years ago we made a proteomic screening of proteins in glia at different stages of devel-opment and found that a small, conserved protein Macrophage migration inhibitory factor (MIF), was expressed in these cells but that the expression differed between the glial cells and between developmental stages.
We have also made a 2-yeast hybrid screen for binding partners to MIF and verified three new such binding partner. A manuscript about the function of one such binding partner, HTRA1 is right now accepted with minor revisions in the journal “Cellular and Molecular life Science”. Since the function of MIF and its binding partner HTRA1 was little known in the nervous sys-tem we started to investigate MIF more and started several collaborations:
The role of MIF in CNS development and regeneration:
Resent studies have shown that MIF may be involved in several neurodegenerative diseases. Among them, Parkinson’s disease, multiple sclerosis and Alzheimers diseases. We are therefore trying to understand what MIF does in both development and regeneration in the CNS and PNS. The research is divided into 5 subprojects:
1. The function of MIF in the CNS development and regeneration: We are investi-gating the function of MIF in vitro in different types of cell culture. To date our preliminary data show that MIF is in fact involved in oligodendrocyte precursor proliferation, oligoden-drocyte myelination and axonal growth, via different receptors. We have continued to in-vestigate this in vivo in a model of de- and re-generation, though the study of this model has just started.
2. The role of MIF in the generation of dopaminergic neurons from iPS cells. In collaboration with Dr. Morten Meyer we are also investigating the effect of MIF on neu-ronal stem cells. Interestingly, MIF increases the development of neuronal precusors to do-paminergic cells. We will continue investigating the mechanisms behind the increase in this phenotype during 2017.
3. The role of MIF in the regeneration of in the spinal cord: Together with Dr. James St John at Griffith University, Australia, we are investigation the function of MIF and HTRA1 in olfactory glia. The group of Dr. St John works with regeneration of the spi-nal cord using olfactory glia for the repair. In this project we have found that MIF positive olfactory glia are more prone to help the regeneration than the ones that do not express the molecule. The mechanisms behind this will be further investigated.
4. The role of MIF in the regeneration in healthy and diabetic peripheral nerve. This is in collaboration with Professor Lars Dahlin at Lund University. We have found that MIF increases during the later stages of regeneration in the PNS, indicating that it may be involved in the start of the myelination process and/or the neuronal target recognition. Interestingly, Schwann cells have several types of MIF receptors and our pre-liminary data show that different receptors (involved in different functions) may be ex-pressed during regeneration as well as during PNS development.
5. The role of MIF and HTRA1 as diagnostic tools in MS. In collaboration with Pro-fessors Zsolt Illes and Jan Lycke, we are investigating MIF and HTRA1 in the serum and cerebrospinal fluid (CSF) of MS patients in different stages of disease. So far we have inves-tigated patients during a relapse and in remission and compared to health controls. Inter-estingly, we have found that that MIF decreases in the MS patients compared to control and that HTRA1 increases. The two proteins correlate well to each other suggesting the binding may be important in the disease. It also suggests that the two proteins may be used as biomarkers. We are at the moment analyzing serum and CSF from secondary progres-sive patients.
Key publications (last 10 years):
List of Peer Reviewed Publications-Åsa Fex Svenningsen Ph.D. In all 33 Peer reviewd publications, two reviews
1. Opioid precursor protein isoform is targeted to the cell nuclei in the human brain. Ko-nonenko O, Bazov I, Watanabe H, Gerashchenko G, Dyachok O, Verbeek DS, Alkass K, Druid H, Andersson M, Mulder J, Svenningsen ÅF, Rajkowska G, Stockmeier CA, Krishtal O, Yakovleva T, Bakalkin G. Biochim Biophys Acta. Biochim Biophys Acta. 2017 Feb;1861(2):246-255.
2. Genetic ablation of soluble TNF does not affect lesion size and functional recovery after moderate spinal cord injury in mice. Ditte Gry Ellman, Hans Gram Novrup, Louise Helskov Jørgensen, Matilda Degn, Lujitha Suntharalingam, Minna Christiansen Lund, Asa Fex-Svenningsen, Roberta Brambilla, Kate Lykke Lambertsen, Bettina Hjelm Clausen, and Simon Bertram Flæng Mediators of Inflammation. 2016;2016:2684098.
3. The Schizophrenia Susceptibility Gene ZNF804A is highly expressed during brain devel-opment, particularly in growth cones. Katja Hvid Hinna; Karen Rich; Åsa Fex-Svenningsen; Eirikur Benedikz PLoS One. 2015 Jul 6;10(7):e0132456.
4. GABA and its B-receptor are present at the node of Ranvier in a small population of sensory fibers, implicating a role in myelination. M. Corell, G. Wicher, K. J. Radomska, E. D. Dağlıkoca, R. Elberg Godskesen, R. Fredriksson, E. Benedikz, V. Magnaghi, Å. Fex Svenningsen. 2015 Feb;93(2):285-95.
5. Oxaliplatin-Induced Neuropathy in Colorectal Cancer: Many Questions With Few An-swers. H. Zedan, T. Frøstrup Hansen, A. Fex Svenningsen, O. J. Vilholm. Clinical Colo-rectal Cancer 2014 Jun;13(2):73-80.
6. Repair of the Peripheral Nerve—Remyelination that Works. Å. Fex Svennigsen, L. B Dahlin Brain Sci. 2013 Aug 2;3(3):1182-97.
7. MALDI mass spectrometry based molecular phenotyping of CNS glial cells for predic-tion in mammalian brain tissue. J. Hanrieder, G. Wicher, J. Bergquist, M. Andersson, A. Fex-Svenningsen. Analytical and Bioanalytical Chemistry 2011 Jul;401(1):135-47.
8. Effects on DHEA levels by estrogen in rat astrocytes and CNS co-cultures via the regula-tion of CYP7B1-mediated metabolism. A. Fex Svenningsen, G. Wicher, J. Lundqvist, H. Pettersson, M.l Corell, M. Norlin. Neurochemistry International 2011 May;58(6):620-4.
9. A low ethanol dose affects all types of cells in mixed long-term embryonic cultures of the cerebellum. C. Pickering, G. Wicher, S. Rosendahl, H. B Schiöth, A. Fex Svenningsen. Basic & Clinical Pharmacology & Toxicology 2010 Aug 15;88(11):2338-49.
10. Optimization of chemically defined cell culture media--replacing fetal bovine serum in mammalian in vitro methods. J van der Valk, D Brunner, K De Smet, A Fex Svenning-sen, P Honegger, L E Knudsen, T Lindl, J Noraberg, A Price, M L Scarino, G Gstraun-thaler. Toxicology in Vitro 2010 Jun;24(4):1053-63.
11. Spatiotemporal Distribution and Function of N-Cadherin in Postnatal Schwann Cells: A Matter of Adhesion? M. Corell, G. Wicher, C. Limbach, M. W. Kilimann, D. R Colman, A. Fex Svenningsen. Journal of Neuroscience Research 2010 Aug 15;88(11):2338-49.
12. In Vitro Neurotoxicity of PBDE-99: Immediate and Concentration-Dependent Effects on Protein Expression in Cerebral Cortex Cells. H. Alm, B. Scholz, K. Kultima, A. Nilsson, P. E. Andrén, M. M Savitski, A. Bergman, M. Stigson, A. Fex-Svenningsen, L. Dencker. Journal of Proteome Research 2010 Mar 5;9(3):1226-35.
13. MDMA (Ecstasy) decreases the number of neurons and stem cells in embryonic cortical cultures. Kindlundh-Högberg, C. Pickering, G. Wicher, D. Hobér, H. B. Schiöth, A. Fex Svenningsen. Cellular and Molecular Neurobiology. 2010 Jan;30(1):13-21.
14. Extracellular clusterin promotes neuronal network complexity in vitro. G. Wicher, A. Fex-Svenningsen, I. Velsecchi, Y. Charnay, H. Aldskogius. Neuroreport.2008 Oct 8;19(15):1487-91
15. Environmental cues from CNS, PNS, and ENS cells regulate CNS progenitor differentiation
A: K. Brännvall, M. Corell, K.Forsberg-Nilsson, A. Fex Svenningsen. Neuroreport Neuroreport. 2008 Aug 27;19(13)
16. Exposure to brominated flame retardant PBDE-99 affects cytoskeletal protein expres-sion in the neonatal mouse cerebral cortex. H. Alm, K. Kultima, B. Scholz, A.Nilsson, P. E. Andrén, A. Fex-Svenningsen, L. Dencker, M. Stigson. Neurotoxicology. 2008 Jul;29(4):628-37.
17. Microfluidic high viability neural cell separation using viscoelastically tuned hydrody-namic spreading. Z. Wu, K. Hjort, G. Wicher, A. Fex Svenningsen. Biomed Microde-vices. 2008 Oct;10(5):631-8.
18. The myelin membrane influences the organization of molecules on the axonal surface. L. Pedraza, J. K. Huang, A. F. Svenningsen, D. R. Colman Journal of Neurochemistry. 2008 June (81):68-68.
Submitted:
1. Macrophage Migration Inhibitory Factor (MIF) Modulates Trophic Signaling Through Interaction With Serine Protease HTRA1" Åsa Fex Svenningsen1*, Svenja Lö-ring1,2, Anna Lahn Sørensen1, Ha Uyen Buu Huynh1, Nellie Martin3, Jesper Bonnet Moeller4,5, Simone Hjæresen1, Maria Louise Elkjær3, Uffe Holmskov4, Zsolt Illes3, Malin Andersson6, Solveig Beck Nielsen1, Eirikur Benedikz1,7
Sent: 2/3- 2017 to Cellular and Molecular Life Sciences. Was returned with revisions suggested by reviewers 15/4-2017. Will be sent back to the journal with revisions 15/5-2017
2. Pecanex-like protein 4 (PCNXL4), a DISC1 and ZNF804A interacting protein, may play a role in neurodevelopment. Solveig Beck Nielsena*, Daniel Jung Jensena,c, Åsa Fex Svenningsena, Eirikur Benedikza,b
Sent to BBRC 4/5-2017
Key collaborations:
Danish:
Professor Zsolt Illes (OUH)
Lektor Morten Meyer (SDU)
Professor Tanja Sheldrik Michel (OUH)
Daniel Wustner (SDU)
Winnie Svensdsen (DTU)
International:
Professor Lars Dahlin (Lund University, Sweden)
Lektor Malin Anderson (Uppsala University, Sweden)
Professor Jan Lycke (Sahgrenska Akademy, Göteborg, Sweden)
Lektor Luca Colucci D´Amato (University dela Campaia, Napoli, Italien)
Lektor James St. John (Griffith University, Brisbane Australia)
Infrastructure:
– Primary cell culture: Neurons, all types of glial cells, separately and together (from both PNS and CNS). Myelinating cultures (with oligodendrocytes and Schwann cells is a speciality)
– The generation of human iPS cells (together with Tanja Sheldrik Michels group)
– pPCR, western blott, Immunochmistry, ELISA , Mesoscale, 2yeast hybrid, MST.
– Funktional studies in vitro: studies of migration, proliferation apoptosis and neurite outgrowth
– Cuprizone model (mice)