WNK Signaling Is Involved in Neural Development via Lhx8/Awh Expression

WNK kinase family is conserved among many species and regulates SPAK/OSR1 and ion co-transporters. Some mutations in human WNK1 or WNK4 are associated with Pseudohypoaldosteronism type II, a form of hypertension. WNK is also involved in developmental and cellular processes, but the molecular mechanisms underlying its regulation in these processes remain unknown. Here, we identify a new target gene in WNK signaling, Arrowhead and Lhx8, which is a mammalian homologue of Drosophila Arrowhead. In Drosophila, WNK was shown to genetically interact with Arrowhead. In Wnk1 knockout mice, levels of Lhx8 expression were reduced. Ectopic expression of WNK1, WNK4 or Osr1 in mammalian cells induced the expression of the Lhx8. Moreover, neural specification was inhibited by the knockdown of both Wnk1 and Wnk4 or Lhx8. Drosophila WNK mutant caused defects in axon guidance during embryogenesis. These results suggest that WNK signaling is involved in the morphological and neural development via Lhx8/Arrowhead.WNK激酶家族（WNK kinase family）在多个物种中高度保守，可调控SPAK/OSR1与离子协同转运蛋白。人类WNK1或WNK4的部分突变与II型假性低醛固酮血症（Pseudohypoaldosteronism type II，一种高血压亚型）相关。WNK还参与发育及细胞生理过程，但该家族在上述过程中的调控分子机制仍未明确。本研究鉴定出WNK信号通路的两个新靶基因：Arrowhead与Lhx8，其中Lhx8为果蝇Arrowhead的哺乳动物同源基因。已有研究证实，果蝇体内的WNK可与Arrowhead发生遗传互作。在Wnk1敲除小鼠中，Lhx8的表达水平显著下调。在哺乳动物细胞中异位表达WNK1、WNK4或Osr1，可诱导Lhx8的表达上调。此外，同时敲低Wnk1与Wnk4或Lhx8，会抑制神经特化过程。果蝇WNK突变体在胚胎发育阶段会出现轴突导向缺陷。上述结果表明，WNK信号通路可通过Lhx8/Arrowhead参与形态发生与神经发育过程。