Research Report 2000 - MDC

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the tumor. Only cells from tumors with low malignancy express GABA receptors, and all tumor cell lines which are selected for high proliferative activity lack this receptor. We now have evidence that the brain environment triggers the induction of this receptor and we will test whether interference with receptor activity influences the behavior of the tumor cells. 130 Selected Publications Labrakakis, C., Patt, S., Hartmann J., and Kettenmann H. (1998) Functional GABA A receptors on human glioma cells, Eur. J. Neurosci. 10, 231-238. Lyons, S. A., and Kettenmann H. (1998) Oligodendroglia and microglia are particularly susceptible to combined hypoxia/hypoglycemia injury in vitro, J. Cerbr. Blood Flow Metabolism, 18, 521-530. Draheim H.J., Prinz M., Weber J.R., Weiser T., Kettenmann H., and Hanisch U.-K. (1999) Induction of K + channels in mouse brain microglia: cells aquire responsiveness to pneumococcal cell wall components during late development. Neurosci. 89, 1379-1390. Grosche, J., Matyash, V., Möller, Verkhratsky, A., Reichenbach A., and Kettenmann H. (1999) Microdomains for neuron-glia interaction: parallel fiber signaling to Bergmann glial cells. Nature Neurosci. 2, 139-43. Prinz, M., Kann, O., Draheim, H. Schumann, R., Kettenmann, H., Weber, J. and Hanisch U-K. (1999) Microglial activation by components of Gram-positive and –negative bacteria: Distinct and common routes to the induction of ion channels and cytokines. J. Neuropath and Experimental Neurology. 58, 1078 –1089. Structure of the Group Group leader Prof. Dr. Helmut Kettenmann Assistant to the group leader Meino Gibson Scientists Dr. Uwe-Karsten Hanisch Dr. Anja Hoffmann Dr. Frank Kirchhoff Dr. Christiane Nolte Dr. Vitali Matyash Dr. Katharina Mertsch Dr. Carsten Ohlemeyer Dr. Michaela Schaenke Guest Scientists Dr. Susanne Kuhn Dr. Michael Synowitz Graduate and undergraduate students Clemens Boucsein Georg Häusler Wolfgang Kresse Marina Matyash Angelika Rappert Carola Schipke Daniel Sirtes Anke Witting Technical assistants Silke Fleischhauer Christiane Gras Brigitte Gerlach Gerda Müller Horst Kagelmaker Secretariat Birgit Jarchow Figure 38: A small section of a Bergmann glial process has been reconstructed based on EM data. Within these structures the neuronal elements are embedded and constitute the site of neuron-glia interaction.
Growth Factor and Regeneration Gary R. Lewin We are using sensory neurons of the dorsal root ganglia as a model system to study neuronal specification. Sensory neurons subserve sensations such as touch and pain and we have shown that different members of the neurotrophin family interact with functionally-distinct sensory neurons to regulate the survival and specific functional properties of sensory neurons. We have also established that brain-derived neurotrophic factor (BDNF) regulates the mechanotransduction properties of slowly-adapting sensory neurons, but not their survival (Carroll et al. 1999). Molecular basis of mechanotransduction Our finding that neurotrophins regulate mechanotransduction has led us to concentrate on elucidating the molecular mechanisms underlying mechanotransduction in mammals. Based on a molecular model of mechanotransduction in C.elegans, we want to establish whether mammalian homologues of genes essential for touch sensitivity in C.elegans (the ‘Mec’ genes) also function as part of a mechanotransduction complex in mammals. In my lab, we have carried out in situ hybridization, Northern blotting and immunocytochemical studies that have established that some species homologues are appropriately expressed in dorsal root ganglion neurons (DRG) (Mannsfeldt et al., 1999). Two mammalian homologues of MEC proteins are stomatin, an integral membrane protein, and mdeg, a sodium channel (MEC-2, and MEC- 4 respectively in C.elegans). To test whether such genes are functionally involved in mechanotransduction, we are presently making transgenic mice that overexpress these putative mechanotransduction genes in sensory neurons. In addition to these functional studies, we have recently isolated two novel cDNAs encoding new members of the stomatin family and have found that both are highly expressed by mammalian sensory neurons. We also plan to establish whether these novel genes have a functional role in mechanotransduction. Phase contrast Mdeg immunofluorescence Development of physiologically distinct sensory neurons Using an in vitro electrophysiological preparation, where one can record from identified sensory neurons innervating skin, it is possible to quantify and characterize physiologically distinct sensory neurons. We have taken advantage of this preparation to ask whether different molecules are involved in specifying the numbers of these different receptor types or their properties during development. By taking mice with targeted deletion or replacement of neurotrophins or their receptors, we have been able to show that individual receptor types require individual neurotrophins during their development. In our most recent study carried out in collaboration with Dr. Rüdiger Klein from the EMBL (Heidelberg), we have shown that neurotrophin-4 exclusively supports the survival of one skin receptor type, the D-hair receptor, by activating signalling pathways downstream of the shc binding site on the trk B receptor (Minichiello et al. 1998). In addition to these studies, using patch clamp techniques, we have also recently shown that nociceptive neurons (pain sensing) with different neurotrophic requirements are functionally distinct (Stucky and Lewin, 1999). These studies may be important as we were also able to show that NGF directly regulates the noxious heat sensitivity of some neurons, a mechanism that might be responsible for injury-induced hyperalgesia in humans. Interestingly, the ability of these NGF- and GDNFdependent populations to sprout is also dramatically different (Belyantseva and Lewin, 1999). Figure 39: Photomicrograph of a cultured adult sensory neuron. The cell has been stained with an antibody directed against the ectodomain of the mdeg channel, a putative mechanotransducing channel. Note that this channel is localized in microdomains on axonal membranes. 131
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Research Report 2000 Covers the Per
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Molecular Therapy Molecular and Dev
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The quantum theory, that provided a
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Introduction Clinical Research The
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Genome Research in Berlin- Brandenb
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External Evaluation Over the period
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Congresses In the years reported, t
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Awards A number of prestigious priz
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Genetics, Bioinformatics and Struct
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disorders. Various MDC groups have
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Steen R.G., Kwitek-Black A.E., Glen
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Selected Publications Binas, B., Da
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Technology transfer Based on the fu
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Selected Publications Müller, D.N.
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Selected Publications Hennies, H.C.
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Somatic genetic alterations in brea
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Clinical and Molecular Genetics of
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Selected Publications Toka, H.R., B
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Lbx1, c-met and the control of cell
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Selected Publications Moore, A., Mc
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Selected Publications Herz, J., Wil
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We aim to study the genetic epidemi
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Nucleation Nucleation as a pre-requ
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Selected Publications Damaschun, G.
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Selected Publications Yuan, T., Wal
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stability. By determining the struc
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Role of Protein Dynamics in Enzyme
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Modeling Nucleic Acid Structure and
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Conformation, Stability and Interac
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Protein Structure Analysis and Prot
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Cell Growth and Differentiation 61
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dendritic cells (DC). Adoptive tran
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developmental pathway that may invo
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Regulation of Transcription in Mamm
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Differentiation and Growth Control
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Cell cycle-dependent transcriptiona
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Cell Cycle Regulation Hans-Dieter R
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Epithelial Differentiation, Invasio
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Selected Publications Hartmann, G.,
Page 79 and 80: Selected Publications Behrens, J.,
Page 81 and 82: Selected Publications Karsten, U.,
Page 83 and 84: Depressed contractility in human he
Page 85 and 86: Understanding calcium handling prot
Page 87 and 88: VSMCs. We have cloned and character
Page 89 and 90: Surgical Oncology Peter M. Schlag T
Page 91 and 92: Ubiquitin System and Endoplasmic Re
Page 93 and 94: P450 Cytochromes and the Endoplasmi
Page 95 and 96: Vascular Biology Hermann Haller Thi
Page 97 and 98: Selected Publications Gollasch, M.,
Page 99 and 100: Electron Microscopy Members of the
Page 101 and 102: Molecular Therapy 101
Page 103 and 104: Hematology, Oncology and Tumor Immu
Page 105 and 106: Selected Publications Sturm, I., K
Page 107 and 108: Selected Publications Westermann, J
Page 109 and 110: fractions. The hematopoietic potent
Page 111 and 112: Interaction of pharmacologically ac
Page 113 and 114: Molecular Basis of Congestive Heart
Page 115 and 116: Selected Publications Schneider, G.
Page 117 and 118: different murine and human tumor ce
Page 119 and 120: Molecular and Cell Biology of Hemat
Page 121 and 122: Phospholipids Dietrich Arndt Cytoto
Page 123 and 124: Regulation and Deregulation of Cell
Page 125 and 126: Evolution, Regulation and Genetic A
Page 127 and 128: Molecular and Developmental Neurosc
Page 129: Cellular Neurosciences Helmut Kette
Page 133 and 134: Synapse Formation and Function Fran
Page 135 and 136: Developmental Neurobiology Fritz G.
Page 137 and 138: Selected Publications Volkmer, H.,
Page 139 and 140: Structure and Organization 139
Page 141 and 142: Prof. Dr. Hans Meyer President of t
Page 143 and 144: Supporting Divisions Safety The div
Page 145 and 146: Press and Public Relations Research
Page 147 and 148: Purchasing and Materials Management
Page 149 and 150: Computing The computing group of th
Page 151 and 152: Awards Thomas Biederer Boehringer-M
Page 153 and 154: Index A Abdul, Yetunde 90 Aguirre-A
Page 155 and 156: H Haase, Hannelore 85, 97, 100, 142
Page 157 and 158: Q Qin, Zhihai 107, 117 Quass, Petra
Page 159: Board of Trustees Chair Wolf-Michae
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