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The role of Tao Kinase in cytoskeletal regulation of dendrite plasticity and function in Drosophila melanogaster
Die Rolle der Tao Kinase in der cytoskeletalen Regulation der dendritischen Plastizität und Funktion in Drosophila melanogaster
Dokument 1.pdf (8.207 KB)
Dendriten, Tao, Cytoskelett, s6k, Drosophila
Freie Schlagwörter (Englisch):
dendrite, Tao, cytoskeletons, s6k, Drosophila
Kneussel, Matthias (Prof. Dr.)
Tag der mündlichen Prüfung:
Kurzfassung auf Englisch:
The proper formation and maintenance of dendritic fields is crucial for the establishment of neuronal circuits. Yet the mechanisms regulating dendritic morphogenesis remain unclear. By studying Drosophila dendritic arborization (da) neurons, I discovered that the conserved STE-20 family kinase Tao is bi-directionally regulating dendritic complexity. Loss of function or RNAi mediated knockdown of Tao kinase increased both dendritic length and the number of dendritic terminals, which can be rescued by transgenic overexpression of Drosophila Tao or human Taok2. Tao function requires its kinase activity as inactive Drosophila or human Taok2 variants were unable to rescue the over-branching phenotype, implying that Tao limits dendritic growth in a kinase activity dependent manner. Conversely, overexpression of wild type or constitutively active Tao limited dendritic growth and generation of terminal branches. These arborization defects were already visible in early neuronal development and live imaging showed that manipulation of Tao kinase activity affects dendritic terminal stability. Correspondingly, disruption of Tao kinase in da neurons resulted in cytoskeletal changes affecting F-actin and microtubule binding protein levels and distribution. In addition, in vivo microtubule tracking showed that the number, polarity and velocity of growing microtubules, which are crucial for dendritic stability, was altered suggesting that Tao kinase limits dendrite development by regulating cytoskeletal dynamics.
Despite the opposite dendritic phenotypes caused by reducing or enhancing Tao function in Class IV (C4da) neurons, both manipulations resulted in similar C4da specific behavioral defect in nociceptive responses. This could in part be explained by Tao level dependent changes in the distribution and/or levels of the mechanosensory channels Piezo and ppk26 in C4da neurons. Additionally, optogenetic activation of C4da neurons showed that Tao knockdown but not overexpression caused impaired nociceptive behavior indicating that the loss of Tao is causing synaptic transmission defects. Correspondingly, ectopic axonal terminals of C4da neurons were observed in Tao mutant C4da neurons suggesting Tao also regulates axonal and synaptic development and maintenance.
Screening for molecular interactors which participate into Tao mediated dendrite development uncovered S6-kinase (S6K) as a candidate, which is negatively regulated by Tao activity to limit dendritic arborization. Collectively, I showed that the conserved Tao kinase in Drosophila is linking to S6K function to limit sensory neuron dendritic arborization and alterations in Tao activity affect neuronal function by disrupting cytoskeletal dynamics and mechanosensitive ion-channel expression and localization.