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Schwann cells are the glial cells of the peripheral nervous system (PNS) with multifunctional roles. Myelinating Schwann cells wrap axons with multilayered myelin sheaths providing electrical insulation and rapid impulse propagation. They also play a key role in the immune response after nerve injury and play an active role during nerve repair by contributing to a surrounding growth environment that allows peripheral nerve axons to regenerate (Rodrigues, Rodrigues et al. 2012). GDF-15, a neurotrophic factor and member of the TGF-β superfamily has been shown to support nerve regeneration (Mensching, Borger et al. 2012; Charalambous, Wang et al. 2013). Schwann cells express GDF-15 and seem to be an important source of GDF 15 in peripheral nerves (Strelau, Strzelczyk et al. 2009). Interestingly, analysis of GDF-15 deficient mice showed a severe and progressive motoneuron loss accompanied by a loss of axons. Moreover, studies in our laboratory showed a hypermyelination in adult mutant mice (Dr. J. Strelau, unpublished data). Together these data suggest that GDF-15 affects Schwann cell. In this study, I first investigated the putative effect of GDF-15 deficiency on Schwann cells and showed for the first time that GDF-15 loss reduces Schwann cell numbers in adult mice. To address the question whether this observation is correlated with an up or down regulation of other important signaling molecules I analyzed several gene expression patterns in adult peripheral nerves and spinal marrow associated with Schwann cells and/or GDF-15. Interestingly, IL-6 expression, a key regulator of the immune response is upregulated in peripheral nerves. However, in vitro studies failed to proof the direct effect of GDF-15 knockdown on IL-6 expression in Schwann cells. For functional studies including GDF-15 dependent proliferation, cell death and migration of Schwann cells I next established a method to produce highly enriched adult Schwann cell cultures, showing that GDF-15 is a survival factor for Schwann cells and that GDF-15 deficient Schwann cells fail to migrate. Both defects were rescued by treatment with recombinant GDF-15. Since GDF-15 specific receptors are not unequivocally identified, I began to investigate the underlying signaling cascades well known to control myelin sheath growth, most notably the putative interaction of GDF-15 with ErbB2 receptor tyrosine kinase, expressed on Schwann cells. Here I showed the activation of the ErbB2 receptor by recombinant GDF-15 in Schwann cells for the first time. Taken together, this suggests that GDF-15 constitutes an important endogenous regulator of Schwann cell functions in the adult.
|Supervisor:||Bading, Prof. Dr. Hilmar|
|Date of thesis defense:||13 February 2014|
|Date Deposited:||17 Feb 2014 15:09|
|Faculties / Institutes:||The Faculty of Bio Sciences > Dean's Office of the Faculty of Bio Sciences|
|Subjects:||500 Natural sciences and mathematics
570 Life sciences