PAR‐1 promotes microtubule breakdown during dendrite pruning in Drosophila

Abstract

Pruning of unspecific neurites is an important mechanism during neuronal morphogenesis. sensory neurons prune their dendrites during metamorphosis. Pruning dendrites are severed in their proximal regions. Prior to severing, dendritic microtubules undergo local disassembly, and dendrites thin extensively through local endocytosis. Microtubule disassembly requires a katanin homologue, but the signals initiating microtubule breakdown are not known. Here, we show that the kinase PAR-1 is required for pruning and dendritic microtubule breakdown. Our data show that neurons lacking PAR-1 fail to break down dendritic microtubules, and PAR-1 is required for an increase in neuronal microtubule dynamics at the onset of metamorphosis. Mammalian PAR-1 is a known Tau kinase, and genetic interactions suggest that PAR-1 promotes microtubule breakdown largely via inhibition of Tau also in Finally, PAR-1 is also required for dendritic thinning, suggesting that microtubule breakdown might precede ensuing plasma membrane alterations. Our results shed light on the signaling cascades and epistatic relationships involved in neurite destabilization during dendrite pruning.

Spatial regulation of microtubule disruption during dendrite pruning in Drosophila

“…PAR-1 activity is often induced by phosphorylation. Our previous data suggested that PAR-1 is specifically activated for microtubule disassembly at the onset of the pupal phase, possibly by ecdysone (Herzmann et al, 2017). It is therefore plausible that the signal emanating from the soma is activated PAR-1.…”

“…These observations are consistent with a microtubule-destabilizing signal emanating from the soma. We previously showed that microtubule disassembly is induced by PAR-1-mediated Tau inhibition (Herzmann et al, 2017). PAR-1 activity is often induced by phosphorylation.…”

“…Plasma membrane retrieval through increased local endocytosis also contributes to thinning of proximal dendrites (Kanamori et al, 2015). Live imaging and genetic data suggest that local microtubule breakdown precedes membrane thinning (Herzmann et al, 2017;Kanamori et al, 2015). Microtubule disassembly is therefore the earliest known local sign of dendrite pruning.…”

“…Microtubule disassembly is therefore the earliest known local sign of dendrite pruning. Microtubule disassembly requires the kinase PAR-1, which mediates inhibition of the microtubule-associated protein Tau (Herzmann et al, 2017). Furthermore, dendrite pruning also requires the microtubule-severing enzyme Katanin p60-like 1 (Kat-60L1) (Lee et al, 2009), possibly also downstream of PAR-1 and Tau (Herzmann et al, 2017).…”

Drosophilamodel of Anti-retroviral therapy Induced Peripheral Neuropathy and Nociceptive Hypersensitivity

“…Because time-lapse imaging revealed that terminal dendrites of neurons exposed to AZT were more dynamic, we wondered whether the instability of dendrites might contribute to their fragmentation. To test this hypothesis, we genetically manipulated the stability of dendrites by modulating the levels of Par-1 kinase, a microtubule-associated serine-threonine kinase whose levels are important in regulating dendritic stability during development 72 . During normal development of dendrites, an increase in Par-1 kinase leads to a decreased stability of dendrites and vice versa.…”