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UNC-116 和 UNC-16 与 NEKL-3 激酶一起发挥作用，促进轴突靶向。

UNC-116 and UNC-16 function with the NEKL-3 kinase to promote axon targeting.

机构信息

Department of Biological Sciences, University of Wisconsin-Milwaukee, Milwaukee, WI 53201, USA.

出版信息

Development. 2023 Sep 15;150(18). doi: 10.1242/dev.201654. Epub 2023 Sep 27.

DOI:10.1242/dev.201654
PMID:37756604
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10561693/
Abstract

KIF5C is a kinesin-1 heavy chain that has been associated with neurodevelopmental disorders. Although the roles of kinesin-1 in axon transport are well known, little is known about how it regulates axon targeting. We report that UNC-116/KIF5C functions with the NEKL-3/NEK6/7 kinase to promote axon targeting in Caenorhabditis elegans. Loss of UNC-116 causes the axon to overshoot its target and UNC-116 gain-of-function causes premature axon termination. We find that loss of the UNC-16/JIP3 kinesin-1 cargo adaptor disrupts axon termination, but loss of kinesin-1 light chain function does not affect axon termination. Genetic analysis indicates that UNC-16 functions with the NEKL-3 kinase to promote axon termination. Consistent with this observation, imaging experiments indicate that loss of UNC-16 and UNC-116 disrupt localization of NEKL-3 in the axon. Moreover, genetic interactions suggest that NEKL-3 promotes axon termination by functioning with RPM-1, a ubiquitin ligase that regulates microtubule stability in the growth cone. These observations support a model where UNC-116 functions with UNC-16 to promote localization of NEKL-3 in the axon. NEKL-3, in turn, functions with the RPM-1 ubiquitin ligase to promote axon termination.

摘要

KIF5C 是一种驱动蛋白-1 重链，与神经发育障碍有关。虽然驱动蛋白-1 在轴突运输中的作用已被广泛研究，但对于其如何调节轴突靶向的机制知之甚少。我们报告 UNC-116/KIF5C 与 NEKL-3/NEK6/7 激酶一起发挥作用，促进秀丽隐杆线虫的轴突靶向。UNC-116 的缺失会导致轴突过度靶向其目标，而 UNC-116 的功能获得会导致轴突过早终止。我们发现 UNC-16/JIP3 驱动蛋白-1 货物衔接蛋白的缺失会破坏轴突终止，但驱动蛋白-1 轻链功能的缺失不会影响轴突终止。遗传分析表明 UNC-16 与 NEKL-3 激酶一起促进轴突终止。与这一观察结果一致，成像实验表明 UNC-16 和 UNC-116 的缺失会破坏 NEKL-3 在轴突中的定位。此外，遗传相互作用表明 NEKL-3 通过与 RPM-1 相互作用促进轴突终止，RPM-1 是一种泛素连接酶，可调节生长锥中的微管稳定性。这些观察结果支持 UNC-116 通过 UNC-16 促进 NEKL-3 在轴突中定位的模型。NEKL-3 反过来与 RPM-1 泛素连接酶一起促进轴突终止。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c8/10561693/f3f0e86fd61f/develop-150-201654-g7.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c8/10561693/f3f0e86fd61f/develop-150-201654-g7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/e6c8/10561693/18a867b8819b/develop-150-201654-g1.jpg
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