Protein phosphatase PP2A regulates microtubule orientation and dendrite pruning in Drosophila

Abstract

Pruning that selectively eliminates inappropriate projections is crucial for sculpting neural circuits during development. During Drosophila metamorphosis, ddaC sensory neurons undergo dendrite-specific pruning in response to the steroid hormone ecdysone. However, the understanding of the molecular mechanisms underlying dendrite pruning remains incomplete. Here, we show that protein phosphatase 2A (PP2A) is required for dendrite pruning. The catalytic (Microtubule star/Mts), scaffolding (PP2A-29B), and two regulatory subunits (Widerborst/Wdb and Twins/Tws) play important roles in dendrite pruning. Functional analyses indicate that PP2A, via Wdb, facilitates the expression of Sox14 and Mical prior to dendrite pruning. Furthermore, PP2A, via Tws, governs the minus-end-out orientation of microtubules (MTs) in the dendrites. Moreover, the levels of Klp10A, a MT depolymerase, increase when PP2A is compromised. Attenuation of Klp10A fully rescues the MT orientation defects in mts or pp2a-29b RNAi ddaC neurons, suggesting that PP2A governs dendritic MT orientation by suppressing Klp10A levels and/or function. Taken together, this study sheds light on a novel function of PP2A in regulating dendrite pruning and dendritic MT polarity in sensory neurons.

An Efficient Screen for Cell-Intrinsic Factors Identifies the Chaperonin CCT and Multiple Conserved Mechanisms as Mediating Dendrite Morphogenesis

“…Similarly, overexpression of ppp2r2b, the human ortholog of twins, suppresses dendritic outgrowth in rat hippocampal neurons, evidencing functional conservation of how the PP2A complex regulates dendritic morphology (Dickey and Strack, 2011) and demonstrating a crucial role for the PP2A holoenzyme in dendritic development. The finding in dendritic growth is consistent with recent reports that also suggest the involvement of the PP2A complex in dendrite pruning (Rui et al, 2020;Wolterhoff et al, 2020). The PP2A complex is known to be involved in various signaling pathways to regulate diverse cellular processes (Casso et al, 2008;Shi, 2009;Zhang et al, 2009).…”

A systematic analysis of microtubule‐destabilizing factors during dendrite pruning in Drosophila

“…I, J Quantification of dendrite severing defects and unpruned dendrite lengths at 16-h APF. Efa6 is dispensable for microtubule orientation but important for microtubule growth in the dendrites of ddaC neurons Microtubule-associated proteins have been recently reported to regulate dendritic microtubule polarity and dendrite pruning in ddaC neurons (Herzmann et al, 2018;Wang et al, 2019;Rui et al, 2020;Tang et al, 2020). To examine the potential involvement of Efa6 in microtubule orientation, we first examined the distribution of dendritic and axonal microtubule markers, Nod-b-Gal and Kinb-Gal, respectively.…”

Spatiotemporal changes in microtubule dynamics during dendritic morphogenesis

“…MT dynamics also play an important role in dendrite pruning of Drosophila C4da neurons [ 38–44 ], a process where the dendritic arbour is selectively removed without causing cell death [ 45 ]. Although large-scale dendritic pruning of C4da neurons happens during metamorphosis (at early pupal stages), which is distinct from earlier dendrite development, the abundance and polarity of dynamic MTs is critical for this process.…”

“…In addition, MT polarity is also likely a major spatial determinant of degeneration, since mutations that alter dendritic MT orientation (e.g. kinesin-1/2, PP2A-Mts-Tws-Klp10A) cause a delay or block of C4da neuron dendrite pruning [ 38–41 ]. Importantly, the sites of initial neurite degeneration and the observed directionality of MT loss correlate with MT organization in neurites.…”