B6 - Kuner

Semaphorins and their receptors, plexins, are key regulators of neuronal development and axonal pathfinding. In contrast to the well-characterized plexin A family, very little was known until recently about the Plexin-B family proteins and their roles in the developing nervous system. In the recent years, we have worked on addressing the molecular components of the Plexin-B receptor complex and addressed the expression of diverse Plexin-B family members as well as their ligands in the developing nervous system. During the last funding period, we generated transgenic mice globally lacking either of the two neuronally-expressed Plexin-B family members, Plexin-B1 and Plexin-B2. Analysis of global knockout mice revealed that Plexin-B2 is critically required for normal pattering of the brain and for neuronal migration during embryonal development. In contrast, Plexin-B1 knockout mice only showed minor defects during embryonic development, which were corrected over later developmental stages. Furthermore, analysis of both mutants showed that B-type plexins play an important role in cortical genesis, in determining the cytoarchitecture of hippocampal neurons and in epithelial-mesenchymal interactions during organogenesis outside of the nervous system. However, it is likely that the redundant expression of Plexin-B1 and Plexin-B2 in a majority of regions in the developing central nervous system occluded the resulting phenotypes in single-deletion mutants. Moreover, the lethality of global Plexin-B2 knockout mice at birth prevented analysis of functions during postnatal development.

In order to understand their primary in vivo functions more precisely and free of secondary artefacts, we now propose to generate and analyze conditional region-specific double-deletion mutants of Plexin-B1 and -B2. During the last funding period, in collaboration with the group of Stefan Offermanns, we generated mice carrying floxed alleles for Plexin-B2. Using mice expressing the Cre recombinase in a spatially- and temporally-restricted manner during this funding period, we plan to study the role of Plexin-B1 and -B2 in the development of the spinal sensory-motor system and the development of the hippocampus. Particular emphasis will be placed on addressing the development of afferent connectivity and the determination of neuronal specification in the dorsal root ganglia and the spinal cord. In a parallel project, we plan on analyzing the in vivo development of the hippocampus and its connectivity and the analysis of the role of B-type plexins in synaptic transmission and hippocampal learning tasks. These integrated approaches will provide insights into the significance of B-type plexins and their semaphorin ligands in the patterning of the peripheral and central nervous system.

Plexine der B-Familie dienen als Rezeptoren der Klasse IV Semaphorine und spielen eine wichtige Rolle bei diversen Entwicklungsprozessen. Bei unseren vorausgegangenen Analysen klassischer Knockout Mausmutanten fanden wir eine wichtige funktionelle Rolle von Plexin-B Proteinen bei der neuronalen Migration und Anordnung im Gehirn. Bedingt durch die postnatale Letalität bei globaler Gendeletion sowie funktioneller Redundanz der beiden Plexine B1 und B2 war eine vollständige Funktionsanalyse nicht möglich. Daher sollen in diesem Projekt anhand konditionaler, Region-spezifischer Doppeldeletions-Mausmutanten von Plexin-B1 und Plexin-B2 die Entwicklungsfunktionen bei der Zellspezifikation, Anordnung und Konnektivität des sensomotorischen Systems und des Hippokampus analysiert werden.

Own project-related publications since the last application (2005)

Deng, S., Hirschberg, A., Worzfeld, T., Penachioni, J.Y., Korostylev, A., Swiercz, J.M., Vodrazka, P., Mauti, O., Stoeckli, E.T., Tamagnone, L., Offermanns S., and Kuner, R. (2007). Plexin-B2, but not Plexin-B1, critically modulates neuronal migration and patterning of the developing nervous system in vivo. J. Neurosci. 27: 6333-6347

Zuliani, C., Kleber, S., Klussmann, S., Wenger, T., Kenzelmann, M., Schreglmann, N., Martinez, A., Del Rio, J.A., Soriano, E., Vodrazka, P., Kuner, R., Groene, H.J., Herr, I., Krammer, P.H., and Martin-Villalba, A. (2005). Control of neuronal branching by the death receptor CD95 (Fas/Apo-1). Cell Death Differ. 13: 31-34

Liu, Y., Yang, F.C., Okuda, T., Dong, X., Zylka, M.J., Chen, C.L., Anderson, D.J., Kuner, R., and Ma, Q. (2008). Mechanisms of compartmentalized expression of Mrg class G-protein-coupled sensory receptors. J. Neurosci. 28: 125-132

Own project-related publications (submitted / in preparation)

Hirschberg, A., Deng, S., Costa, M., Friedel, R., Maier, V., Korostylev, A., Worzfeld, T., Vodrazka, P., Swiercz, J.M., Götz, M., Offermanns, S., and Kuner, R. A critical role for Sema4D-Plexin-B interactions in corticogenesis. In preparation.

Vodrazka, P., Korostylev, A., Swiercz, J.M., Worzfeld, T., Deng, S., Fazzari, P., Hirschberg, A., Tamagnone, L., Offermanns, S., and Kuner, R. The Sema4D-Plexin-B signaling complex regulates dendritic complexity in developing neurons via diverse pathways. Eur. J. Neurosci., in revision

Korostylev, A., Worzfeld, T., Deng, S., Friedel, R.H., Swiercz, J.M., Vodrazka, P., Maier, V., Hirschberg, A., Ohoka, Y., Inagaki, S., Offermanns, S., and Kuner, R. A functional role for Semaphorin 4D-Plexin-B1 interactions in epithelial branching morphogenesis during organogenesis. Development, in revision

Own project-related publications prior to 2005

Worzfeld, T., Püschel, A., Offermanns, S., and Kuner, R. (2004). Plexin-B family members demonstrate non-redundant expression patterns in the developing mouse nervous system: A anatomical basis for morphogenetic effects of Sema4D during development. Eur. J. Neurosci. 19: 2622-2632

Swiercz, J.M., Kuner, R., Behrens, J., and Offermanns, S. (2002). Plexin-B1 directly interacts with PDZ-RhoGEF/LARG to regulate RhoA and growth cone morphology. Neuron 35: 51-63

Kuner, R., Swiercz, J.M., Zywietz, A., Tappe, A., and Offermanns, S. (2002). Characterization of the expression of PDZ-RhoGEF, LARG and Galpha12/Galpha13 proteins in the murine nervous system. Eur. J. Neurosci. 16: 2333-2341

Agarwal, N., Offermanns, S., and Kuner, R. (2004). Conditional gene targeting in neurons of the dorsal root ganglia and trigeminal ganglia. Genesis 38/3: 122-129

Swiercz, J.M., Kuner, R., and Offermanns, S. (2004). Plexin-B1/RhoGEF-mediated RhoA activation involves the receptor tyrosine kinase ErbB-2. J. Cell Biol. 165: 869-880

Selected publications from other projects outside the SFB since 2005

Kuner, R., Groom, A., Bresink, I., Kornau, H.C., Stefovska, V., Müller, G., Hartmann, B., Tschauner, K., Waibel, S., Ludolph, A.C., Ikonomidou, C., Seeburg, P.H., and Turski, L. (2005). Late-onset motoneuron disease caused by transgenic expression of a functionally modified AMPA receptor subunit. Proc. Natl. Acad. Sci. USA 102: 5826-5831

Tappe, A., and Kuner, R. (2006). Regulation of motor performance and striatal function by synaptic scaffolding proteins of the Homer1 family. Proc. Natl. Acad. Sci. USA 103: 774-779

Tappe, A., Klugmann, M., Luo, C., Hirlinger, D., Agarwal, N., Benrath, J., Ehrengruber, M.U., During, M.J., and Kuner, R. (2006). Synaptic scaffolding protein Homer1a protects against chronic inflammatory pain. Nat. Med. 12: 677-681

Pareek, T.K., Keller, J., Kesavapany, S., Agarwal, N., Kuner, R., Pant, H.C., Iadarola, M.J., Brady, R.O., and Kulkarni, A.B. (2006). Cyclin-dependent kinase 5 modulates nociceptive signaling through direct phosphorylation of transient receptor potential vanilloid 1. Proc. Natl. Acad. Sci. USA 104: 660-665

Michalski, C.W., Laukert, T., Sauliunaite, D., Pacher, P., Bergmann, F., Agarwal, N., Su, Y., Giese, T., Giese, N.A., Bátkai, S., Friess, H., and Kuner, R. (2007). Cannabinoids ameliorate pain and reduce disease pathology in caerulein-induced acute pancreatitis. Gastroenterology 132: 1968-1978

Tappe-Theodor, A., Agarwal, N., Katona, I., Rubino, T., Martini, L., Swiercz, J.M., Mackie, K., Monyer, H., Parolaro, D., Whistler, J., Kuner, T., and Kuner, R. (2007). A molecular basis of analgesic tolerance to cannabinoids. J. Neurosci. 27: 4165-4177

Agarwal, N., Pacher, P., Tegeder, I., Amaya, F., Constantin, C., Brenner, G.J., Rubino, T., Michalski, C.W., Marsicano, G., Monory, K., Mackie, K., Marian, C., Batkai, S., Parolaro, D., Fischer, M.J., Reeh, P., Kunos, G., Kress, M., Lutz, B., Woolf, C.J., and Kuner, R. (2007). Nociceptor-specific conditional gene deletion reveals that cannabinoids mediate analgesia largely via peripheral type 1 cannabinoid receptors. Nat. Neurosci. 10: 870-879

Rohini Kuner

Pharmakologisches Institut

Universität Heidelberg

Im Neuenheimer Feld 366

69120 Heidelberg

Phone:  06221-548289
Fax:      06221-548549

email:    rohini.kuner(at)pharma.uni-heidelberg.de