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Structure of the Group Group Leader Prof. Gary R. Lewin Scientists Dr. Jing Hu Dr. Alexey Kozlenkov Dr. Stefan Lechner Dr. Ewan St. John Smith* Dr. Christiane Wetzel* Graduate Students Gireesh Anirudhan Nevena Milenkovic Alexandra Seifert Li-Yang Chiang Sören Markworth Rui Wang Liudmilla Lapatsina* Henning Frenzel* Technical Assistants Anke Scheer Heike Thränhardt Anja Wegner Secretariat Manuela Brandenburg * part of the period reported Comparison of TRPV1 positive fibers in the superficial dorsal horn of the mouse (left) and from the naked mole rat (right). Note that more TRPV1 positive profiles are observed in the ventral region of the dorsal horn in the naked mole rat compared to the mouse dorsal spinal cord (indicated with green boxes). Scale bar 100µm. duction in the inner ear may also be required for normal cutaneous sensation. Our data indicate that members of the unconventional myosin protein family have a common function in sensory neurons and in hair cells, mechanotransducing cells of the inner ear. In both cell types these proteins may function to regulate the adaptation of the mechanotransduction channels. We are currently working on further hearing genes that may also affect cutaneous mechanosensation. The same genes as we study in the mouse are also mutated in humans and it is possible that the perception of cutaneous touch stimuli is altered in such patients. We are now measuring pyschometric functions in normals and hearing impaired people in order to describe quantitatively potential differences in the perception of touch. The Naked Mole Rat a pain free mammal? In collaboration with Dr Thomas Park at the University of Illinois we have been characterizing the somatosensory system of the naked mole rat (Heterocepahlus glabor). The naked mole rat is an unusual subterranean rodent in many respects. It is the only known poikilothermic mammal (ie. cold blooded), it lives in colonies with an insect-like social structure, and it is also the longest-lived rodent species known (lifetimes in excess of 25 yrs). Thomas Park noted previously that the sensory innervation of the skin in these mammals is devoid of two major neuropeptides, Substance P and Calcitonin gene related peptide. Since these two peptides are involved in nociception we have made a detailed study of pain related behaviors in this species. Interestingly, although this animal has normal acute pain responses it displays no hypersensitivity (so called hyperalgesia) to a variety of inflammatory and chemical stimuli. We suspect that at the heart of this specialized adaptation lies distinct gene variants encoding ion channels and associated channels that are required for the transduction of painful stimuli. We are at present cloning and characterizing genes coding ion channels from the naked mole rat to address this issue. We have already cloned and started to characterize the naked mole rat capsaicin receptor, an ion channel called TRPV1. Interestingly, naked mole rats have no behavioral response to the noxious compound capsaicin, which produces the “hot” sensation of chilli peppers. Nevertheless the naked mole rat TRPV1 receptor can be potently activated by capsaicin. It appears that naked mole rat sensory fibers are in fact differently connected in the dorsal spinal cord compared to other rodents. Selected Publications Milenkovic N, Frahm C, Gassmann M, Griffel C, Erdmann B, Birchmeier C, Lewin GR, Garratt AN (2007) Nociceptive tuning by Stem Cell Factor/c-Kit signaling. Neuron (in press). Martinez-Salgado C, Benckendorff AG, Chiang LY, Wang R, Milenkovic N, Wetzel C, Hu J, Stucky CL, Parra MG, Mohandas N, Lewin GR (2007) Stomatin and sensory neuron mechanotransduction. J Neurophys (in press). Wetzel C, Hu J, Riethmacher D, Benckendorff A, Harder L, Eilers A, Moshourab R, Kozlenkov A, Labuz D, Caspani O, Erdmann B, Machelska H, Heppenstall PA, Lewin GR (2007) A stomatindomain protein essential for touch sensation in the mouse. Nature 445:206-209. Hu J, Milenkovic N, Lewin GR (2006) The high threshold mechanotransducer: a status report. Pain 120,3-7. Hu J, Lewin GR (2006) Mechanosensitive currents in the neurites of cultured mouse sensory neurones. J Physiol 577,815-828. 174 Function and Dysfunction of the Nervous System
Mitochondrial Dynamics Christiane Alexander M y group is studying disease genes that are essential for the integrity of mitochondria. Mitochondria depend on their ability to form a dynamic network. Fusion and fission events of the mitochondrial inner and outer membranes provide the molecular basics for such dynamics to occur. Genes like OPA1 (optic atrophy 1) and MFN2 (mitofusin 2) are important for the fusion of the mitochondrial membranes as well as the adaptation of the shape and the ultra-structure of mitochondria membranes. Mutations in these genes lead to neurological disorders such as autosomal dominant optic atrophy (adOA) and Charcot-Marie Tooth disease (CMT). We are studying the function of these genes with the help of animal models, cell culture and biochemical approaches. The expression of OPA1 is regulated via alternative splicing, polyadenylation and proteolytic processing Vasudheva Rheddy Akepati, Maja Fiket The OPA1 protein is a dynamin-related large GTPase, which is associated with the inner mitochondrial membrane, facing the inter-membrane space. By positional cloning, we were able to identify the OPA1 gene, which spans about 100 kb of genomic sequence and is divided into 31 exons. Alternative splicing of OPA1 leads to the generation of a set of splice variants present in each cell of a given organism. We discovered that during evolution, the number of alternative splice variants increased from 1 transcript in yeast, 2 splice forms in Drosophila, 4 splice forms in mice to 8 forms in humans. Moreover, the 3’UTR of OPA1 transcripts in mammals contains multiple polyadenylation sites, which may serve to confer differences in mRNA stability or translational efficiency to the various isoforms. After translation, proteolytic cleavage by different mitochondrial proteases further adds to the very complex regulation of the OPA1 protein. Complete loss of OPA1 causes dramatic changes in mitochondrial morphology, lack of respiration and a block in fusion. Our work showed that isoform 1 is the most abundant form at transcript and protein level. Therefore, we propose that this form represents the ancient form of OPA1. Loss of OPA1 leads to loss of cristae, respiration and mitochondrial fusion in mice Maja Fiket In order to study the physiological function of OPA1 in mice, we mutated the OPA1 gene by homologous recombination. OPA1 +/- mice are phenotypically indistinguishable from wildtype littermates, but OPA1 -/- embryos are reduced in size and die during gastrulation. We observed that mitochondria of OPA1 -/- embryos are completely fragmented. Similarly, mouse embryonic fibroblasts derived from OPA1 -/- embryos display fragmented mitochondria with abnormal inner membrane morphology that are respiration and fusion deficient. OPA1 -/- fibroblasts are less sensitive to staurosporineinduced apoptosis and do not undergo cytochrome c release. Transfection of OPA1 -/- fibroblasts with a cDNA encoding the mouse homologue of human OPA1 isoform 1 restores respiratory chain activity, mitochondrial membrane potential, tubular morphology and fusion of the mitochondrial network. These reconstitution experiments assigned thus distinct functions to one particular OPA1 isoform. Manipulation of OPA1 affects fly neuroblasts and glial cells but not neurons Susanne Lorenz Flies contain only two different isoforms of OPA1: a short and a long form. Loss of OPA1 in the fly leads to similar lethal effects during development as observed in mice. OPA1 deficient flies do not pupate and stop growth at the early third instar larval stage. Molecular transgenic techniques allowed us to limit the expression of OPA1 transgenes in the fly eye. The remaining tissues contained normal OPA1 levels and garanteed for the rest of the fly’s body to develop normally. We observed that the individual expression of the short, long and mutated forms of OPA1 in either the eye imaginal disc or just the photoreceptors of the fly eye produced different phenotypical outcomes. A devastating effect on proliferation in pre-mitotic tissue was noticed after driving the expression of the short form or a mutant form of OPA1. In contrast, post-mitotic photoreceptor cells slowly degenerated after over-expression of the long form or the mutated form. Further, we noticed a special sensitivity of neuroblasts and glial cells to the over- Function and Dysfunction of the Nervous System 175
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Research Report 2008 MDC Berlin-Buc
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