Dokument

Zusammenfassung:
Die Fusion der Myoblasten ist ein fundamentaler Prozess bei der Muskelbildung multizellulärer Organismen. Ein hierfür gut untersuchter Modellorganismus ist Drosophila melanogaster, bei welchem die Bildung der somatischen Muskulatur durch die Fusion von Founderzellen (FCs) und fusionskompetenten Myoblasten (FCMs) vollzogen wird. Das eigentliche Fusionsereignis wird durch das spezifische Erkennen und die Adhäsion der beiden Zellpopulationen mit Hilfe der Transmembranproteine eingeleitet. Anschließend wird das Signal intrazellulär an das Aktin-Zytoskelett weitergeleitet, was die Bildung der Fusionsporen und die Verschmelzung der Membranen zur Folge hat. Dabei wird an der Kontaktstelle der fusionierenden Myoblasten ein Adhäsionsring gebildet, in dessen Mitte sich ein Aktin-reiches Zentrum befindet (Kesper et al., 2007). Lebend-Untersuchungen haben gezeigt, dass sich dieser Aktin-Plaque sehr dynamisch verhält und innerhalb von zwei Minuten seine maximale Größe erreicht. Die Auflösung der Plaques dauert nur eine Minute. Mutantenanalysen zeigen, dass die Arp2/3-abhängige Aktin-Polymerisation essentiell für die Myoblastenfusion ist. Die Dynamik der Aktin-Plaques lässt zudem vermuten, dass die Depolymerisation ebenfalls eine entscheidende Rolle spielt. Um diese F-Aktin-basierten Prozesse genauer zu analysieren, wurden in dieser Arbeit mehrere Ansätze verfolgt. Die Arp2/3-abhängige Aktin-Plaque Bildung wird durch die NPFs Scar/Wave und WASP in FCs und FCMs reguliert. Mutationen in der Scar/Wave- als auch der WASP-abhängigen Arp2/3-Aktivierung resultieren in einer Reduktion der Aktin-Plaques, aber nicht in einem Verlust der Aktin-Plaque Bildung (diese Arbeit, Sens et al., 2010). Es wurde daher in dieser Arbeit nach weiteren Komponenten gesucht, die an der Aktin-Plaque Bildung beteiligt sind, wie z.B. das Aktinmonomer-bindende Protein Profilin/Chic (Chic). Die hier durchgeführten Dosisexperimente und Protein-Interaktionsstudien deuten daraufhin, dass Chic sowohl eine Komponente der Scar/Wave- als auch der WASP-abhängigen Aktin-Polymerisation ist. Des Weiteren konnte in diesem Zusammenhang der Arp2/3-Regulator Ena/VASP als eine mögliche neue Komponente der Arp2/3-vermittelten Aktin-Polymerisation während der Myoblastenfusion und der Muskelanheftung identifiziert werden. Ein weiterer Teil meiner Arbeit befasst sich mit der Aktivierung des Scar-Komplexes während der Myoblastenfusion. Dieser erfolgt durch die kleine Rho GTPase Rac bzw. durch ein Zusammenwirken von Rac mit den Komponenten des pentameren Scar-Komplexes. In Drosophila gibt es drei Rac GTPasen, von denen Rac1 und Rac2 während der Myoblastenfusion redundant wirken. Die Expression der konstitutiv-aktiven und dominant-negativen Konstrukte von Rac1 resultiert in einem starken Fusionsphänotyp. Auch die Doppelmutanten für rac1- und rac2 zeigen unfusionierte Myoblasten. In allen Mutanten konnte ich noch die Bildung von Aktin-Plaques beobachten. Zudem zeigen die in dieser Arbeit durchgeführten biochemischen und genetischen Interaktionsstudien eine Interaktion von Rac mit Chic, Scar/Wave, Sra-1 und Kette. Um Aktivatoren bzw. Inaktivatoren für die beiden Rac GTPasen aufzudecken, wurde unter Verwendung der aktivierten Form von Rac1 und Rac2 ein globaler Hefe-2-Hybrid Screen durchgeführt. Unter den potentiellen Interaktionspartnern für Rac1 während der Myoblastenfusion konnten die Csk-Kinase und das Aktin-bindende Protein WupA identifiziert werden. Der letzte Teil dieser Arbeit befasst sich mit der Suche nach Aktin-depolymerisierenden Komponenten, die am Membranzusammenbruch während der Fusion beteiligt sind. Dabei wurden Mutationen im Depolymerisierungsfaktor Cofilin/Twinstar (Tsr) auf Fusionsstörungen untersucht. Weder homozygote tsr-Mutanten zeigten Defekte in der Fusion der Myoblasten, noch die Expression von aktivierten bzw. inaktiviertem Tsr in Myoblasten. Daraufhin wurde ein weiterer Kofaktor, Aip1/Flare (Flr), bezüglich seiner mRNA-Expression analysiert und Doppelmutantenanalysen mit tsr durchgeführt. Die Lokalisation des flr Transkripts konnte dabei in der embryonalen somatischen Muskulatur nachgewiesen werden, sowie auch in den Ovarien, im Testis und in den Imaginalscheiben. Allerdings zeigen flr-Einzelmutanten keine Muskeldefekte. In tsr;flr-Doppelmutanten konnten jedoch schwache Muskelstörungen beobachtet werden, was auf ein potentielles Zusammenwirken der beiden Proteine während der Muskelbildung hindeutet. Zusammenfassend lässt sich aus diesen Ergebnissen postulieren, dass Tsr in funktioneller Redundanz mit weiteren depolymerisierenden Proteinen wirkt.

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