Overexpression of KLF genes in retinal ganglion cells

Adult mammalian CNS neurons undergo a developmental switch in intrinsic axon growth ability associated with their failure to regenerate axons after injury. Krüppel-like transcription factors (KLF) regulate intrinsic axon growth ability, but signaling regulation upstream and downstream is poorly understood. Here we find that suppressing expression of KLF9, an axon growth suppressor normally upregulated 250-fold in retinal ganglion cell (RGC) development, promotes long-distance optic nerve regeneration in vivo. We identify a novel binding partner, MAPK10/JNK3, critical for KLF9’s axon growth suppressive activity. Additionally, by screening genes regulated by KLFs in RGCs, we identify dual-specificity phosphatase 14 (Dusp14) as key to limiting axon growth and regenerative ability downstream of KLF9, associated with its dephosphorylation of MAPKs critical to neurotrophic signaling of RGC axon elongation. These results now link intrinsic and extrinsic regulation of axon growth and suggest new therapeutic strategies to promote axon regeneration in the adult CNS.成年哺乳动物中枢神经系统（Central Nervous System, CNS）神经元会经历一次内在轴突生长能力的发育转变，这一转变与其损伤后无法再生轴突密切相关。Krüppel样转录因子（Krüppel-like transcription factors, KLF）可调控内在轴突生长能力，但目前对其上下游的信号调控机制仍知之甚少。本研究发现，抑制KLF9的表达可促进体内长距离视神经再生；KLF9作为一种轴突生长抑制因子，在视网膜神经节细胞（retinal ganglion cell, RGC）发育过程中其表达通常会上调250倍。我们鉴定出一种新型结合蛋白MAPK10/JNK3，其对KLF9的轴突生长抑制活性至关重要。此外，本研究通过筛选视网膜神经节细胞中受KLF家族调控的基因，鉴定出双特异性磷酸酶14（dual-specificity phosphatase 14, Dusp14）是KLF9下游限制轴突生长与再生能力的关键因子，其通过对调控视网膜神经节细胞轴突延伸神经营养信号的关键丝裂原活化蛋白激酶（mitogen-activated protein kinases, MAPKs）进行去磷酸化，进而调控轴突生长。上述研究结果首次将轴突生长的内在与外在调控机制联系起来，并为促进成年哺乳动物中枢神经系统轴突再生提供了全新的治疗策略。