Die Bedeutung der Interaktion vom Cyclase-assoziierten Protein 1 und Cofilin 1 in Wachstumskegeln hippocampaler Neurone
Ein essenzieller Schritt in der Entwicklung des Nervensystems ist die Axonmigration, bei der Axone zu ihrem jeweiligen spezifischen Ziel wandern, um dort synaptische Verknüpfungen herzustellen. Gesteuert wird diese Wanderung durch Wachstumskegel, welche aktinreiche Vorwölbungen an der Spitze von Axo...
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Format: | Doctoral Thesis |
Language: | German |
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Philipps-Universität Marburg
2023
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Online Access: | PDF Full Text |
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An essential step in the development of the nervous system is a process called axon migration, in which axons migrate to their specific target to establish synaptic connections. This migration is controlled by growth cones, which are actin-rich dilated structures at the tip of axons. Growth cones change their structure and direction of movement in response to extracellular signals by re-arranging the actin cytoskeleton. This continuous assembly and disassembly of actin filaments, which is also called actin treadmilling, is regulated by actin-binding proteins. Two important actin-binding proteins are the cyclase-associated protein 1 and cofilin 1. Cofilin 1 accelerates the actin treadmilling by severing and depolymerisation of actin filaments. Cyclase-associated protein 1 promotes actin dynamics by accelerating depolymerisation and the dissociation of cofilin 1 from globular actin and restoring adenosine triphosphate-G-actin. It is also known that cyclase-associated protein 1 and cofilin 1 cooperate synergistically: cyclase-associated protein 1 promotes depolymerization of cofilin 1-decorated actin filaments. However, the knowledge about cyclase-associated protein 1 and cofilin 1 in growth cones is not yet fully understood. Therefore, this work investigated the role of cyclase-associated protein 1 and cofilin 1 in growth cones. In this study, the single knockout of cyclase-associated protein 1 or cofilin1 as well as the double-knockout of cyclase-associated protein 1 and cofilin 1 led to a reduction of actin dynamics and an increase of the growth cone area. These results can most likely be explained by the fact that the knockout of cyclase-associated protein 1 and/or cofilin 1 leads to a disturbance of the actin treadmilling. Due to the predominance of actin filament stabilization and the accumulation of cofilin 1-G-actin-complexes, the growth cone area is increased. Overexpression of cyclase-associated protein 1 and cofilin 1 in double knockout cells led to a rescue of the original growth cone size. But overexpression of cofilin 1 and a cyclase-associated protein 1-mutant, which cannot interact with cofilin 1, failed in rescuing the growth cone area. That confirms the central importance of the interaction of these two proteins in maintaining the growth cone area. In summary, cyclase-associated protein 1 and cofilin 1 and their interaction play a central role in the regulation of actin dynamics in growth cones. This evidence for the physiological relevance of the interaction of those two ABPs should increase our knowledge of the mechanisms of actin dynamis for a better understanding of actin-dependent pathologies.