Neurobiology Section, Biological Sciences Division, University of California San Diego, La Jolla, CA 92093.
Neurobiology Section, Biological Sciences Division, University of California San Diego, La Jolla, CA 92093
Proc Natl Acad Sci U S A. 2020 Jul 28;117(30):18037-18048. doi: 10.1073/pnas.1921878117. Epub 2020 Jul 8.
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 (, 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 or single knockout, double knockout, and knockin, the postcrossing spinal cord commissural axons are disorganized and showed anterior-posterior guidance errors after midline crossing. Growth cones from either knockout or 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 double knockout or 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 ( cause axon guidance defects in development.
轴突-轴突相互作用对于神经系统布线过程中的轴突导向至关重要。然而，目前尚不清楚生长锥在感知和响应导向线索时彼此之间是如何进行通信的。我们发现帕金森病基因富亮氨酸重复激酶 2 (LRRK2) 在生长锥-生长锥通信中具有意想不到的作用。LRRK2 蛋白作为支架，通过招募其他激酶间接诱导 Frizzled3 过度磷酸化，也可直接在苏氨酸 598 (T598) 上磷酸化 Frizzled3。在 或 单敲除、 双敲除和 敲入模型中，穿越后的脊髓连合轴突排列紊乱，中线穿越后出现前后导向错误。来自 敲除或 敲入小鼠的生长锥显示出相互作用的改变，表明通讯受损。Frizzled3 和 Vangl2 之间的细胞间相互作用对于平面细胞极性信号转导至关重要。我们在这里表明，这种相互作用受 Frizzled3 在 T598 处的磷酸化调节，并且可以由 LRRK2 以激酶活性依赖性方式进行调节。在 双敲除或 敲入模型中，中脑多巴胺能轴突束明显变宽且排列紊乱，表现出异常的后向生长。我们的研究结果表明，LRRK2 调节轴突导向中的生长锥-生长锥通信，并且功能丧失突变和功能获得性突变 ( 均会导致发育中的轴突导向缺陷。
