of the Max - MDC

Structure of the Group
Group Leader
Prof. Dr. Dr. Thomas J. Jentsch
Scientists
Dr. Muriel Auberson
Dr. Jens Fuhrmann
Dr. Ioana Neagoe
Dr. Gaia Novarino
Dr. Vanessa Plans
Dr. York Rudhard*
Dr. Olaf Scheel*
Dr. Guillermo Spitzmaul*
Dr. Tobias Stauber*
Dr. Rubén Vicente García
Dr. Vitya Vardanyan*
Dr. Stefanie Weinert*
Dr. Anselm Zdebik
Graduate Students
Eun-yeong Bergsdorf*
Gwendolyn Billig*
Judith Blanz*
Matthias Heidenreich*
Maren Knoke
Philipp Lange
Lilia Leisle*
Tanja Maritzen*
Carsten Pfeffer
Patricia Preston
Marco Rust*
Gesa Rickheit
Lena Wartosch
Figure 1. Organ of Corti in WT
mice (above) and knock-in mice
hererozygous for a dominant
negative point mutation in the
potassium channel KCNQ4 that
we had identified in human
DFNA2 deafness (below). Basal
cochlear turns from 1-year-old
mice are shown. Sensory outer
hair cells (OHCs) are stained in
green for the motor protein prestin,
while red staining represents
calretinin, a marker for
sensory inner hair cells (IHCs).
The dominant negative mutation
in KCNQ4 leads to a selective
loss of outer hair cells, which
explains the slowly progressive
hearing loss that attains about
60 dB.
role of luminal chloride for endosomes and lysosomes. This
finding may profoundly change our view of the role of luminal
pH in the endosomal/lysosomal system.
ClC-2 – a plasma membrane Cl - channel important
for CNS myelin
Judith Blanz, Michaela Schweizer, Muriel Auberson,
Hannes Maier, Christian Hübner
We had previously shown that disruption of the widely
expressed plasma membrane chloride channel ClC-2 entails
blindness and male infertility. We now found that these
mice also present with widespread vacuolation of the white
matter of the CNS. Electron microscopy revealed vacuolation
within the myelin sheaths with which oligodendrocytes
enwrap axons. Central nerve conduction velocity was
reduced, but there was no conspicuous neurological phenotype.
We hypothesize that ClC-2 has a role in extracellular
ion homeostasis. ClC-2 is a candidate gene for mild forms of
human leukoencephalopathy, although our initial mutational
screening of patients was inconclusive.
KCC potassium-chloride cotransporters
ClC-7/Ostm1, is not associated with neuronal cell loss.
Whereas the deposits in ClC-7 and Ostm1 KO mice are found
in neuronal cell bodies, they localize to initial axon segments
in Clcn6 -/- mice. The mild behavioural phenotype of
mice lacking ClC-6 includes a reduction in pain sensitivity
that is probably caused by massive intracellular deposits in
dorsal root ganglia.
Endosomal ClC-4 and ClC-5 mediate electrogenic
Cl - /H + -exchange
Anselm Zdebik, Olaf Scheel, Eun-Yeong Bergsdorf
Similar to the bacterial EcClC-1 protein, and in contrast to
their previous classification as Cl - -channels, ClC-4 and ClC-5
are antiporters that exchange chloride for protons. This discovery
is surprising as such transporters, while still supporting
endosomal acidification, will partially dissipate the pH
gradient across endosomal membranes. Both ClC-4 and ClC-
5 lose their coupling to protons when a key residue, the
‘gating glutamate’, is neutralized by mutagenesis. The coupling
of chloride to proton fluxes may indicate an important
Electroneutral potassium-chloride cotransport is mediated
by four different KCC isoforms (KCC1 – KCC4), all of which
were disrupted in our laboratory. KCC2 is the main determinant
of the developmental ‘GABA-switch’ that establishes
the inhibitory effect of the neurotransmitters GABA and
glycine by lowering the intraneuronal Cl—concentration.
Disruption of KCC4 led to deafness and renal tubular
acidosis.
KCC3 KO mice display neurogenic hypertension
Marco Rust, Jörg Faulhaber, Carsten Pfeffer, Rudolf
Schubert, Heimo Ehmke, Christian Hübner
KCC3 is mutated in the human Anderman syndrome which is
associated with a severe neurodegeneration. Our KO mouse
replicated this phenotype and additional revealed a slowly
progressive hearing loss. We now investigated the basis of
the arterial hypertension of these animals. We disproved the
hypothesis that it is caused by an altered vascular contractility
and showed that it is of neurogenic origin.
54 Cardiovascular and Metabolic Disease Research