Center for Biological Signaling Studies

Freiburg, Germany

Center for Biological Signaling Studies

Freiburg, Germany
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Schwenk J.,Albert Ludwigs University of Freiburg | Schwenk J.,Center for Biological Signaling Studies | Harmel N.,Sensory Medical | Brechet A.,Albert Ludwigs University of Freiburg | And 14 more authors.
Neuron | Year: 2012

AMPA-type glutamate receptors (AMPARs) are responsible for a variety of processes in the mammalian brain including fast excitatory neurotransmission, postsynaptic plasticity, or synapse development. Here, with comprehensive and quantitative proteomic analyses, we demonstrate that native AMPARs are macromolecular complexes with a large molecular diversity. This diversity results from coassembly of the known AMPAR subunits, pore-forming GluA and three types of auxiliary proteins, with 21 additional constituents, mostly secreted proteins or transmembrane proteins of different classes. Their integration at distinct abundance and stability establishes the heteromultimeric architecture of native AMPAR complexes: a defined core with a variable periphery resulting in an apparent molecular mass between 0.6 and 1 MDa. The additional constituents change the gating properties of AMPARs and provide links to the protein dynamics fundamental for the complex role of AMPARs in formation and operation of glutamatergic synapses.

Bettler B.,University of Basel | Fakler B.,Albert Ludwigs University of Freiburg | Fakler B.,Center for Biological Signaling Studies
Current Opinion in Neurobiology | Year: 2017

Ionotropic AMPA-type glutamate receptors and G-protein-coupled metabotropic GABAB receptors are key elements of neurotransmission whose cellular functions are determined by their protein constituents. Over the past couple of years unbiased proteomic approaches identified comprehensive sets of protein building blocks of these two types of neurotransmitter receptors in the brain (termed receptor proteomes). This provided the opportunity to match receptor proteomes with receptor physiology and to study the structural organization, regulation and function of native receptor complexes in an unprecedented manner. In this review we discuss the principles of receptor architecture and regulation emerging from the functional characterization of the proteomes of AMPA and GABAB receptors. We also highlight progress in unraveling the role of unexpected protein components for receptor physiology. © 2017 Elsevier Ltd

Slanchev K.,Albert Ludwigs University of Freiburg | Putz M.,Albert Ludwigs University of Freiburg | Schmitt A.,Albert Ludwigs University of Freiburg | Kramer-Zucker A.,Albert Ludwigs University of Freiburg | And 2 more authors.
Human Molecular Genetics | Year: 2011

NPHP4 mutations cause nephronophthisis, an autosomal recessive cystic kidney disease associated with renal fibrosis and kidney failure. The NPHP4 gene product nephrocystin-4 interacts with other nephrocystins, cytoskeletal and ciliary proteins; however, the molecular and cellular functions of nephrocystin-4 have remained elusive. Here we demonstrate that nephrocystin-4 is required for normal cloaca formation during zebrafish embryogenesis. Time-lapse imaging of the developing zebrafish pronephros revealed that tubular epithelial cells at the distal pronephros actively migrate between the yolk sac extension and the blood island towards the ventral fin fold to join the proctodeum and to form the cloaca. Nphp4-deficient pronephric duct cells failed to connect with their ectodermal counterparts, and instead formed a vesicle at the obstructed end of the pronephric duct. Nephrocystin-4 interacts with nephrocystin-1 and Par6. Depletion of zebrafish NPHP1 (nphp1) increased the incidence of cyst formation and randomization of the normal body axis, but did not augment cloaca malformation in nphp4-deficient zebrafish embryos. However, simultaneous depletion of zebrafish Par6 (pard6) aggravated cloaca formation defects in nphp4-depleted embryos, suggesting that nphp4 orchestrates directed cell migration and cloaca formation through interaction with the Par protein complex. © The Author 2011. Published by Oxford University Press. All rights reserved.

Lienkamp S.S.,Albert Ludwigs University of Freiburg | Lienkamp S.S.,Center for Biological Signaling Studies
Seminars in Cell and Developmental Biology | Year: 2016

Modern sequencing technology is revolutionizing our knowledge of inherited kidney disease. However, the molecular role of genes affected by the rapidly rising number of identified mutations is lagging behind. Xenopus is a highly useful, but underutilized model organism with unique properties excellently suited to decipher the molecular mechanisms of kidney development and disease. The embryonic kidney (pronephros) can be manipulated on only one side of the animal and its formation observed directly through the translucent skin. The moderate evolutionary distance between Xenopus and humans is a huge advantage for studying basic principles of kidney development, but still allows us to analyze the function of disease related genes. Optogenetic manipulations and genome editing by CRISPR/Cas are exciting additions to the toolbox for disease modelling and will facilitate the use of Xenopus in translational research. Therefore, the future of Xenopus in kidney research is bright. © 2016 Elsevier Ltd.

Ganal S.C.,Albert Ludwigs University of Freiburg | Sanos S.L.,Albert Ludwigs University of Freiburg | Sanos S.L.,Bavarian Nordic | Kallfass C.,Albert Ludwigs University of Freiburg | And 9 more authors.
Immunity | Year: 2012

Mononuclear phagocytes are an important component of an innate immune system perceived as a system ready to react upon encounter of pathogens. Here, we show that in response to microbial stimulation, mononuclear phagocytes residing in nonmucosal lymphoid organs of germ-free mice failed to induce expression of a set of inflammatory response genes, including those encoding the various type I interferons (IFN-I). Consequently, NK cell priming and antiviral immunity were severely compromised. Whereas pattern recognition receptor signaling and nuclear translocation of the transcription factors NF-κB and IRF3 were normal in mononuclear phagocytes of germ-free mice, binding to their respective cytokine promoters was impaired, which correlated with the absence of activating histone marks. Our data reveal a previously unrecognized role for postnatally colonizing microbiota in the introduction of chromatin level changes in the mononuclear phagocyte system, thereby poising expression of central inflammatory genes to initiate a powerful systemic immune response during viral infection. © 2012 Elsevier Inc.

Solozobova V.,Albert Ludwigs University of Freiburg | Wyvekens N.,Albert Ludwigs University of Freiburg | Pruszak J.,Albert Ludwigs University of Freiburg | Pruszak J.,Center for Biological Signaling Studies
Stem Cell Reviews and Reports | Year: 2012

Pluripotent stem cells offer an abundant and malleable source for the generation of differentiated cells for transplantation as well as for in vitro screens. Patterning and differentiation protocols have been developed to generate neural progeny from human embryonic or induced pluripotent stem cells. However, continued refinement is required to enhance efficiency and to prevent the generation of unwanted cell types. We summarize and interpret insights gained from studies of embryonic neuroepithelium. A multitude of factors including soluble molecules, interactions with the extracellular matrix and neighboring cells cooperate to control neural stem cell self-renewal versus differentiation. Applying these findings and concepts to human stem cell systems in vitro may yield more appropriately patterned cell types for biomedical applications. © 2012 The Author(s).

Klose C.S.N.,Albert Ludwigs University of Freiburg | Hoyler T.,Albert Ludwigs University of Freiburg | Kiss E.A.,Albert Ludwigs University of Freiburg | Tanriver Y.,Albert Ludwigs University of Freiburg | And 2 more authors.
Current Opinion in Immunology | Year: 2012

It has recently emerged that innate lymphocytes are more diverse than previously appreciated. In addition to natural killer cells, various subsets of innate lymphoid cells are now being characterized. It has become apparent that the transcriptional programs underlying lineage specification and cell fate decisions of innate lymphocytes strikingly resemble those of T cell subsets, suggesting that such transcriptional circuitry was already pre-formed in the evolutionary older innate immune system. Here, we will review recent advances in our understanding of the core transcriptional programs driving development and cell fate decisions of innate lymphocytes. We will also discuss whether these transcriptional programs are stable or flexible, thereby allowing for plastic adaptation of immune responses. © 2012 Elsevier Ltd.

Berkefeld H.,Albert Ludwigs University of Freiburg | Fakler B.,Albert Ludwigs University of Freiburg | Fakler B.,Center for Biological Signaling Studies
Journal of Neuroscience | Year: 2013

Large conductance Ca2+- and voltage-activated potassium channels (BKCa) shape neuronal excitability and signal transduction. This reflects the integrated influences of transmembrane voltage and intracellular calcium concentration ([Ca2+]i) that gate the channels. This dual gating has been mainly studied as voltage-triggered gating modulated by defined steady-state [Ca2+]i, a paradigm that does not approximate native conditions. Hereweuse submillisecond changes of [Ca2+]i to investigate the time course of the Ca2+-triggered gating of BKCa channels expressed in Chinese hamster ovary cells at distinct membrane potentials in the physiological range. The results show that Ca2+can effectively gateBKCa channels and that Ca2+gating is largely different from voltage-driven gating. Most prominently, Ca2+ gating displays a pronounced delay in the millisecond range between Ca2+ application and channel opening (pre-onset delay) and exhibits slower kinetics across the entire [Ca2+]i-voltage plane. Both characteristics are selectively altered by co-assembled BKβ4 or an epilepsy-causing mutation that either slows deactivation or speeds activation and reduces the pre-onset delay, respectively. Similarly, co-assembly of the BKCa channels with voltage-activated Ca2+ (Cav) channels, mirroring the native configuration, decreased the preonset delay to submillisecond values. In BKCa-Cav complexes, the time course of the hyperpolarizing K+-current response is dictated by the Ca2+ gating of the BKCa channels. Consistent with Cav-mediated Ca2+ influx, gating was fastest at hyperpolarized potentials, but decreased with depolarization of the membrane potential. Our results demonstrate that under experimental paradigms meant to approximate the physiological conditions BKCa channels primarily operate as ligand-activated channels gated by intracellular Ca2+ and that Ca2+ gating is tuned for fast responses in neuronal BKCa-Cav complexes. © 2013 the authors.

Filippi A.,Albert Ludwigs University of Freiburg | Mueller T.,Albert Ludwigs University of Freiburg | Driever W.,Albert Ludwigs University of Freiburg | Driever W.,Center for Biological Signaling Studies
Journal of Comparative Neurology | Year: 2014

Throughout the vertebrate lineage, dopaminergic neurons form important neuromodulatory systems that influence motor behavior, mood, cognition, and physiology. Studies in mammals have established that dopaminergic neurons often use γ-aminobutyric acid (GABA) or glutamatergic cotransmission during development and physiological function. Here, we analyze vglut2, gad1b and gad2 expression in combination with tyrosine hydroxylase immunoreactivity in 4-day-old larval and 30-day-old juvenile zebrafish brains to determine which dopaminergic and noradrenergic groups may use GABA or glutamate as a second transmitter. Our results show that most dopaminergic neurons also express GABAergic markers, including the dopaminergic groups of the olfactory bulb (homologous to mammalian A16) and the subpallium, the hypothalamic groups (A12, A14), the prethalamic zona incerta group (A13), the preoptic groups (A15), and the pretectal group. Thus, the majority of catecholaminergic neurons are gad1b/2-positive and coexpress GABA. A very few gad1/2-negative dopaminergic groups, however, express vglut2 instead and use glutamate as a second transmitter. These glutamatergic dual transmitter phenotypes are the Orthopedia transcription factor-dependent, A11-type dopaminergic neurons of the posterior tuberculum. All together, our results demonstrate that all catecholaminergic groups in zebrafish are either GABAergic or glutamatergic. Thus, cotransmission of dopamine and noradrenaline with either GABA or glutamate appears to be a regular feature of zebrafish catecholaminergic systems. We compare our results with those that have been described for mammalian systems, discuss the phenomenon of transmitter dualism in the context of developmental specification of GABAergic and glutamatergic regions in the brain, and put this phenomenon in an evolutionary perspective. © 2013 Wiley Periodicals, Inc.

Prinz M.,Albert Ludwigs University of Freiburg | Prinz M.,Center for Biological Signaling Studies | Knobeloch K.-P.,Albert Ludwigs University of Freiburg
Frontiers in Immunology | Year: 2012

Type I interferons (IFNs) were originally identified as antiviral effector molecules that exert pleiotropic physiological processes ranging from immune modulation, control of prolifer-ation, apoptosis to antitumor activity. However, type I IFNs were recently also shown to apply both beneficial and detrimental effects to the central nervous system (CNS) and a tightly balanced equilibrium between cellular activation and inhibition seems to be essential to maintain homeostasis within the CNS. In inflammatory pathologies affecting the CNS, type I IFNs are in the center of attention not only because interferon beta (IFN-β) is used as a standard therapeutic in the treatment of relapsing-remitting multiple sclerosis (MS), but also as type I IFN expression is associated with distinct pathologies. Despite the great efficiency of IFN-β in reducing MS relapses and attenuation of novel inflammatory lesions is well documented, underlying molecular mechanisms and cellular target specificities are just beginning to emerge. In contrast to the curative effects, aberrant activation of the type I IFN response were also recently shown to be associated with detrimental effects exemplified by the Aicardi-Goutières syndrome (AGS), a severe disabling autoimmune inflammatory encephalopathy. This review will highlight the dual role of type I interferons during chronic CNS inflammation. Recently uncovered molecular and cellular mechanisms in the etiology of AGS and experimental autoimmune encephalomyelitis (EAE), the murine model of MS will be highlighted. © 2012 Prinz and Knobeloch.

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