Chuang Marian, Goncharov Alexandr, Wang Shaohe, Oegema Karen, Jin Yishi, Chisholm Andrew D
Section of Neurobiology, Division of Biological Sciences, University of California, San Diego, La Jolla, CA 92093, USA.
Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA.
Cell Rep. 2014 Nov 6;9(3):874-83. doi: 10.1016/j.celrep.2014.09.054. Epub 2014 Oct 23.
Precise regulation of microtubule (MT) dynamics is increasingly recognized as a critical determinant of axon regeneration. In contrast to developing neurons, mature axons exhibit noncentrosomal microtubule nucleation. The factors regulating noncentrosomal MT architecture in axon regeneration remain poorly understood. We report that PTRN-1, the C. elegans member of the Patronin/Nezha/calmodulin- and spectrin-associated protein (CAMSAP) family of microtubule minus-end-binding proteins, is critical for efficient axon regeneration in vivo. ptrn-1-null mutants display generally normal developmental axon outgrowth but significantly impaired regenerative regrowth after laser axotomy. Unexpectedly, mature axons in ptrn-1 mutants display elevated numbers of dynamic axonal MTs before and after injury, suggesting that PTRN-1 inhibits MT dynamics. The CKK domain of PTRN-1 is necessary and sufficient for its functions in axon regeneration and MT dynamics and appears to stabilize MTs independent of minus-end localization. Whereas in developing neurons, PTRN-1 inhibits activity of the DLK-1 mitogen-activated protein kinase (MAPK) cascade, we find that, in regeneration, PTRN-1 and DLK-1 function together to promote axonal regrowth.
微管（MT）动力学的精确调控日益被视为轴突再生的关键决定因素。与发育中的神经元不同，成熟轴突表现出非中心体微管成核。在轴突再生过程中，调节非中心体MT结构的因素仍知之甚少。我们报告称，PTRN-1是线虫中微管负端结合蛋白的Patronin/Nezha/钙调蛋白和血影蛋白相关蛋白（CAMSAP）家族的成员，对体内有效的轴突再生至关重要。ptrn-1基因敲除突变体在发育过程中轴突生长通常正常，但在激光切断轴突后再生性生长明显受损。出乎意料的是，ptrn-1突变体中的成熟轴突在损伤前后动态轴突MT的数量均增加，这表明PTRN-1抑制MT动力学。PTRN-1的CKK结构域对其在轴突再生和MT动力学中的功能是必需且充分的，并且似乎独立于负端定位来稳定MT。在发育中的神经元中，PTRN-1抑制DLK-1丝裂原活化蛋白激酶（MAPK）级联反应的活性，而我们发现，在再生过程中，PTRN-1和DLK-1共同发挥作用以促进轴突再生。
