Temasek Life Sciences Laboratory, 1 Research Link, National University of Singapore, Singapore 117604.
Department of Biological Sciences, National University of Singapore, Singapore 117543.
Development. 2022 Nov 15;149(22). doi: 10.1242/dev.200844. Epub 2022 Nov 16.
The evolutionarily conserved Glycogen Synthase Kinase 3β (GSK3β), a negative regulator of microtubules, is crucial for neuronal polarization, growth and migration during animal development. However, it remains unknown whether GSK3β regulates neuronal pruning, which is a regressive process. Here, we report that the Drosophila GSK3β homologue Shaggy (Sgg) is cell-autonomously required for dendrite pruning of ddaC sensory neurons during metamorphosis. Sgg is necessary and sufficient to promote microtubule depolymerization, turnover and disassembly in the dendrites. Although Sgg is not required for the minus-end-out microtubule orientation in dendrites, hyperactivated Sgg can disturb the dendritic microtubule orientation. Moreover, our pharmacological and genetic data suggest that Sgg is required to promote dendrite pruning at least partly via microtubule disassembly. We show that Sgg and Par-1 kinases act synergistically to promote microtubule disassembly and dendrite pruning. Thus, Sgg and Par-1 might converge on and phosphorylate a common downstream microtubule-associated protein(s) to disassemble microtubules and thereby facilitate dendrite pruning.
在动物发育过程中，进化上保守的糖原合酶激酶 3β（GSK3β）是微管的负调节剂，对于神经元极化、生长和迁移至关重要。然而，GSK3β 是否调节神经元修剪（一种退行性过程）尚不清楚。在这里，我们报告果蝇 GSK3β 同源物 Shaggy（Sgg）在变态期间对于 ddaC 感觉神经元的树突修剪是细胞自主必需的。Sgg 足以促进树突中的微管解聚、周转和解体。尽管 Sgg 对于树突中的负端向外微管取向不是必需的，但过度激活的 Sgg 可以干扰树突微管取向。此外，我们的药理学和遗传学数据表明，Sgg 通过微管解体至少部分地促进树突修剪。我们表明，Sgg 和 Par-1 激酶协同作用以促进微管解聚和树突修剪。因此，Sgg 和 Par-1 可能会汇聚并磷酸化一个共同的下游微管相关蛋白（s）以解聚微管，从而促进树突修剪。
