Axon–axon interactions are essential for axon guidance during nervous system wiring. However, it is unknown whether and how the growth cones communicate with each other while sensing and responding to guidance cues. We found that the Parkinson’s disease gene, leucine-rich repeat kinase 2 (LRRK2), has an unexpected role in growth cone–growth cone communication. The LRRK2 protein acts as a scaffold and induces Frizzled3 hyperphosphorylation indirectly by recruiting other kinases and also directly phosphorylates Frizzled3 on threonine 598 (T598). In LRRK1 or LRRK2 single knockout, LRRK1/2 double knockout, and LRRK2 G2019S knockin, the postcrossing spinal cord commissural axons are disorganized and showed anterior–posterior guidance errors after midline crossing. Growth cones from either LRRK2 knockout or G2019S knockin mice showed altered interactions, suggesting impaired communication. Intercellular interaction between Frizzled3 and Vangl2 is essential for planar cell polarity signaling. We show here that this interaction is regulated by phosphorylation of Frizzled3 at T598 and can be regulated by LRRK2 in a kinase activity-dependent way. In the LRRK1/2 double knockout or LRRK2 G2019S knockin, the dopaminergic axon bundle in the midbrain was significantly widened and appeared disorganized, showing aberrant posterior-directed growth. Our findings demonstrate that LRRK2 regulates growth cone–growth cone communication in axon guidance and that both loss-of-function mutation and a gain-of-function mutation (G2019S) cause axon guidance defects in development.

轴突-轴突相互作用对于神经系统接线过程中的轴突引导至关重要。然而，未知的是，生长锥在感知和响应引导提示时是否以及如何相互通信。我们发现帕金森氏病基因，富含亮氨酸的重复激酶2（LRRK2）在生长锥-生长锥通讯中具有意想不到的作用。LRRK2蛋白充当支架并通过募集其他激酶间接诱导Frizzled3过度磷酸化，并直接在苏氨酸598（T598）上直接磷酸化Frizzled3。在LRRK1或LRRK2单敲除，LRRK1 / 2双敲除和LRRK2 G2019S中敲入后，穿越中线后，穿越后的脊髓连合轴突杂乱无章，显示出前后方向的引导误差。来自LRRK2基因敲除或G2019S基因敲入小鼠的生长锥显示出相互作用的改变，表明沟通受损。Frizzled3和Vangl2之间的细胞间相互作用对于平面细胞极性信号传导至关重要。我们在这里显示，这种相互作用是由在T598处Frizzled3的磷酸化调节的，并且可以由LRRK2以激酶活性依赖性的方式调节。在LRRK1 / 2双敲除或LRRK2 G2019S中敲入后，中脑中的多巴胺能轴突束显着加宽并显得杂乱无章，显示出异常的后向生长。我们的发现表明，LRRK2调节轴突导向中的生长锥-生长锥通讯，并且功能缺失突变和功能获得突变（G2019S）均会引起轴突导向发育中的缺陷。