@article{LeopoldZeilbeckWeberetal.2017, author = {Leopold, Stephanie A. and Zeilbeck, Ludwig F. and Weber, Gregor and Seitz, Roswitha and B{\"o}sl, Michael R. and J{\"a}gle, Herbert and Fuchshofer, Rudolf and Tamm, Ernst R. and Ohlmann, Andreas}, title = {Norrin protects optic nerve axons from degeneration in a mouse model of glaucoma}, series = {Scientific Reports}, volume = {7}, journal = {Scientific Reports}, doi = {10.1038/s41598-017-14423-8}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-173494}, year = {2017}, abstract = {Norrin is a secreted signaling molecule activating the Wnt/β-catenin pathway. Since Norrin protects retinal neurons from experimental acute injury, we were interested to learn if Norrin attenuates chronic damage of retinal ganglion cells (RGC) and their axons in a mouse model of glaucoma. Transgenic mice overexpressing Norrin in the retina (Pax6-Norrin) were generated and crossed with DBA/2J mice with hereditary glaucoma and optic nerve axonal degeneration. One-year old DBA/2J/Pax6-Norrin animals had significantly more surviving optic nerve axons than their DBA/2J littermates. The protective effect correlated with an increase in insulin-like growth factor (IGF)-1 mRNA and an enhanced Akt phosphorylation in DBA/2J/Pax6-Norrin mice. Both mouse strains developed an increase in intraocular pressure during the second half of the first year and marked degenerative changes in chamber angle, ciliary body and iris structure. The degenerations were slightly attenuated in the chamber angle of DBA/2J/Pax6-Norrin mice, which showed a β-catenin increase in the trabecular meshwork. We conclude that high levels of Norrin and the subsequent constitutive activation of Wnt/β-catenin signaling in RGC protect from glaucomatous axonal damage via IGF-1 causing increased activity of PI3K-Akt signaling. Our results identify components of a protective signaling network preventing degeneration of optic nerve axons in glaucoma.}, language = {en} } @article{ElgheznawyOefteringEnglertetal.2023, author = {Elgheznawy, Amro and {\"O}ftering, Patricia and Englert, Maximilian and Mott, Kristina and Kaiser, Friederike and Kusch, Charly and Gbureck, Uwe and B{\"o}sl, Michael R. and Schulze, Harald and Nieswandt, Bernhard and V{\"o}gtle, Timo and Hermanns, Heike M.}, title = {Loss of zinc transporters ZIP1 and ZIP3 augments platelet reactivity in response to thrombin and accelerates thrombus formation in vivo}, series = {Frontiers in Immunology}, volume = {14}, journal = {Frontiers in Immunology}, doi = {10.3389/fimmu.2023.1197894}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-320154}, year = {2023}, abstract = {Zinc (Zn2+) is considered as important mediator of immune cell function, thrombosis and haemostasis. However, our understanding of the transport mechanisms that regulate Zn2+ homeostasis in platelets is limited. Zn2+ transporters, ZIPs and ZnTs, are widely expressed in eukaryotic cells. Using mice globally lacking ZIP1 and ZIP3 (ZIP1/3 DKO), our aim was to explore the potential role of these Zn2+ transporters in maintaining platelet Zn2+ homeostasis and in the regulation of platelet function. While ICP-MS measurements indicated unaltered overall Zn2+ concentrations in platelets of ZIP1/3 DKO mice, we observed a significantly increased content of FluoZin3-stainable free Zn2+, which, however, appears to be released less efficiently upon thrombin-stimulated platelet activation. On the functional level, ZIP1/3 DKO platelets exhibited a hyperactive response towards threshold concentrations of G protein-coupled receptor (GPCR) agonists, while immunoreceptor tyrosine-based activation motif (ITAM)-coupled receptor agonist signalling was unaffected. This resulted in enhanced platelet aggregation towards thrombin, bigger thrombus volume under flow ex vivo and faster in vivo thrombus formation in ZIP1/3 DKO mice. Molecularly, augmented GPCR responses were accompanied by enhanced Ca2+ and PKC, CamKII and ERK1/2 signalling. The current study thereby identifies ZIP1 and ZIP3 as important regulators for the maintenance of platelet Zn2+ homeostasis and function.}, language = {en} } @article{WeiderWegenerSchmittetal.2015, author = {Weider, Matthias and Wegener, Am{\´e}lie and Schmitt, Christian and K{\"u}spert, Melanie and Hillg{\"a}rtner, Simone and B{\"o}sl, Michael R. and Hermans-Borgmeyer, Irm and Nait-Oumesmar, Brahim and Wegner, Michael}, title = {Elevated in vivo levels of a single transcription factor directly convert satellite glia into oligodendrocyte-like cells}, series = {PLoS Genetics}, volume = {11}, journal = {PLoS Genetics}, number = {2}, doi = {10.1371/journal.pgen.1005008}, url = {http://nbn-resolving.de/urn:nbn:de:bvb:20-opus-144123}, pages = {e1005008}, year = {2015}, abstract = {Oligodendrocytes are the myelinating glia of the central nervous system and ensure rapid saltatory conduction. Shortage or loss of these cells leads to severe malfunctions as observed in human leukodystrophies and multiple sclerosis, and their replenishment by reprogramming or cell conversion strategies is an important research aim. Using a transgenic approach we increased levels of the transcription factor Sox10 throughout the mouse embryo and thereby prompted Fabp7-positive glial cells in dorsal root ganglia of the peripheral nervous system to convert into cells with oligodendrocyte characteristics including myelin gene expression. These rarely studied and poorly characterized satellite glia did not go through a classic oligodendrocyte precursor cell stage. Instead, Sox10 directly induced key elements of the regulatory network of differentiating oligodendrocytes, including Olig2, Olig1, Nkx2.2 and Myrf. An upstream enhancer mediated the direct induction of the Olig2 gene. Unlike Sox10, Olig2 was not capable of generating oligodendrocyte-like cells in dorsal root ganglia. Our findings provide proof-of-concept that Sox10 can convert conducive cells into oligodendrocyte-like cells in vivo and delineates options for future therapeutic strategies.}, language = {en} }