Axon morphogenesis and maintenance require an evolutionary conserved safeguard function of Wnk kinases antagonizing Sarm and Axed

• Published in: Neuron (Cambridge, Mass.) Mass.), 2021-09, Vol.109 (18), p.2864-2883.e8
• Main Authors: Izadifar, Azadeh, Courchet, Julien, Virga, Daniel M., Verreet, Tine, Hamilton, Stevie, Ayaz, Derya, Misbaer, Anke, Vandenbogaerde, Sofie, Monteiro, Laloe, Petrovic, Milan, Sachse, Sonja, Yan, Bing, Erfurth, Maria-Luise, Dascenco, Dan, Kise, Yoshiaki, Yan, Jiekun, Edwards-Faret, Gabriela, Lewis, Tommy, Polleux, Franck, Schmucker, Dietmar
• Format: Article
• Language: English
• Subjects: axon branching; axon degeneration; axon maintenance; axon morphogenesis; Cellular Biology; cortical pyramidal neuron; de novo protein synthesis; Drosophila mechanosensory neuron; Life Sciences; Neurobiology; neurodevelopment; Neurons and Cognition; neuroprotection; Wallerian; Wnk kinase
• ISSN: 0896-6273; 1097-4199
• DOI: 10.1016/j.neuron.2021.07.006

The molecular and cellular mechanisms underlying complex axon morphogenesis are still poorly understood. We report a novel, evolutionary conserved function for the Drosophila Wnk kinase (dWnk) and its mammalian orthologs, WNK1 and 2, in axon branching. We uncover that dWnk, together with the neuroprotective factor Nmnat, antagonizes the axon-destabilizing factors D-Sarm and Axundead (Axed) during axon branch growth, revealing a developmental function for these proteins. Overexpression of D-Sarm or Axed results in axon branching defects, which can be blocked by overexpression of dWnk or Nmnat. Surprisingly, Wnk kinases are also required for axon maintenance of adult Drosophila and mouse cortical pyramidal neurons. Requirement of Wnk for axon maintenance is independent of its developmental function. Inactivation of dWnk or mouse Wnk1/2 in mature neurons leads to axon degeneration in the adult brain. Therefore, Wnk kinases are novel signaling components that provide a safeguard function in both developing and adult axons. •Wnk kinases regulate axon branching in fly neurons and mouse cortical pyramidal neurons•Independently, dWnk and WNK1/2 are also constitutively required in adult axon maintenance•dWnk positively supports Nmnat function and suppresses D-Sarm and Axundead•Wnk regulates a conserved network linking axon branching, maintenance, and degeneration Izadifar, Courchet, et al. demonstrate an evolutionary conserved role for Wnk kinases in axon morphogenesis and adult axon maintenance. These dual roles of Wnk kinases involve regulation of components of the Wallerian degeneration network. This study provides evidence for a shared regulatory network linking developmental axon branching, maintenance, and degeneration.