Research Report 2010 - MDC

Dr. Rubén Vicente García*Dr. Stefanie WeinertDr. Anselm Zdebik*Graduate Students/Postdocs after graduationPhilipp Lange*Carsten PfefferLena WartoschGraduate StudentsEun-yeong Bergsdorf*Gwendolyn Billig*Matthias Heidenreich*Sabrina Jabs*Maren Knoke*Lilia Leisle*Kristin Natho*Patricia PrestonGesa Rickheit*Patricia SejaTechnical AssistantsAnyess von Bock*Alexander FastInga Freyert*Nicole KrönkeIna LauterbachRainer LebenJanet LieboldRuth ParejaPatrick Seidler*Stefanie Wernick*Silke ZillmannStudentsVerena Perneczky*Cathleen Rohleder*Florian WagnerResearch CoordinatorDr. Dietmar Zimmer*Animal CarePetra Göritz*SecretariatPia Philippi**part of the period reportedFigure 1. Model for potassium recycling in theinner ear. The fluid space of the scala media isin direct contact with the apical membranesof inner hair cells (shown in green) and outerhair cells (red). Its unusually high K + concentrationand positive voltage (+100 mV), both generatedby the epithelium of the stria vascularis,are needed to drive a depolarizing K + currentthrough mechanosensitive channels intothose sensory hair cells. Potassium then leaveshair cells at their basal pole and is transportedback to the stria.ClC-7 is needed for normal protein degradation inrenal proximal tubulesLena Wartosch, Jens Fuhrmann, Tobias StauberClC-7 is a lysosomal Cl - /H + exchanger broadly distributedacross tissues. We have previously shown that itsdisruption leads to osteopetrosis and lysosomal storagedisease in mice and men. We now generated a conditionalClC-7 KO that allowed us, on the one hand, tofollow the CNS pathology much further and to showthat it is owed to a cell-intrinsic effect on neurons. Toinvestigate the lysosomal storage disease that isobserved in the kidney, we selectively inactivated ClC-7in proximal tubules. Combined endocytosis/proteindegradation experiments in vivo showed for the firsttime that the lack of ClC-7 significantly slows proteindegradation. The enlargement of lysosomal-like compartmentsin KO proximal tubules, however, is not dueto excessive protein accumulation because it could notbe prevented by the simultaneous KO of ClC-5 that iscrucial for endocytotic uptake.Role of the vesicular chloride transporterClC-3 in neuroendocrine cellsTanja Maritzen, Damien Keating, Ioana Neagoe,Anselm ZdebikClC-3 is a Cl - /H + -exchanger that is expressed on endosomesand synaptic vesicles. We have previously shownthat its KO leads to a severe neurodegeneration whichresults in a complete absence of the hippocampus aftera few months. However, ClC-3 is broadly expressed inmany tissues. Newly generated antibodies allowed us forthe first time to investigate its tissue expression byimmunocytochemistry. We found that ClC-3 is highlyexpressed in several neuroendocrine tissues, includingadrenal glands and pancreatic islets, where it isexpressed in all secretory cell types. ClC-3 was detected inendosomes in synaptic-like microvesicles, but not in largedense core vesicles that are responsible e.g. for insulin oradrenalin secretion in β-cells or chromaffin cells, respectively.Nonetheless, stimulated secretion of either hormonewas reduced in ClC-3 KO cells, suggesting an indirecteffect of ClC-3 on large dense core vesicle exocytosis.Function and Dysfunction of the Nervous System 155