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.

复杂轴突形态发生的分子和细胞机制仍然知之甚少。我们报告了果蝇Wnk 激酶 (dWnk) 及其哺乳动物直向同源物 WNK1 和 2 在轴突分支中的一种新的进化保守功能。我们发现 dWnk 与神经保护因子 Nmnat 一起在轴突分支生长过程中拮抗轴突不稳定因子 D-Sarm 和 Axundead (Axed)，揭示了这些蛋白质的发育功能。D-Sarm 或 Axed 的过度表达会导致轴突分支缺陷，这可以通过 dWnk 或 Nmnat 的过度表达来阻止。令人惊讶的是，成年果蝇的轴突维持也需要 Wnk 激酶和小鼠皮质锥体神经元。Wnk 对轴突维护的要求与其发育功能无关。成熟神经元中 dWnk 或小鼠 Wnk1/2 的失活导致成人大脑中的轴突退化。因此，Wnk 激酶是新的信号组件，在发育中和成体轴突中提供保护功能。