The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling.
The Dyslexia-susceptibility Protein KIAA0319 Inhibits Axon Growth Through Smad2 Signaling.
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DOI：
10.1093/cercor/bhx023
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发表时间：
2017-03-01
期刊：
影响因子：
--
通讯作者：
Sousa MM
中科院分区：
文献类型：
--
作者：
Franquinho F;Nogueira-Rodrigues J;Duarte JM;Esteves SS;Carter-Su C;Monaco AP;Molnár Z;Velayos-Baeza A;Brites P;Sousa MM
KIAA0319是一种与阅读障碍相关的跨膜蛋白，可能在神经元迁移中发挥作用。在这里，我们表明KIAA0319的表达不仅限于大脑，也存在于感觉神经元和脊髓神经元中，从出生后早期到成年期增加，并因损伤而下调。这表明KIAA0319参与了与神经元迁移无关的功能。支持这一假设的是，KIAA0319的过表达抑制了海马神经节和背根神经节神经元的轴突生长；KIAA0319的细胞内结构域足以诱导这一效应。在体内观察到类似的抑制作用，因为KIAA0319转导感觉神经元后轴突再生受损。相反，神经元中KIAA0319的缺失在体外增加了轴突的生长，并促进了体内轴突的再生。在机制水平上，KIAA0319通过JAK2-SH2B1途径激活Smad2，Smad2在KIAA0319介导的抑制轴突生长中起核心作用。总之，我们确定KIAA0319是轴突生长和再生中的一个新的参与者，具有抑制轴突的内在生长潜力的能力。本研究描述了外周神经系统和中枢神经系统轴突生长过程中的一种新的调节机制，并为开发有效的促进轴突再生的治疗方法提供了新的靶点。
KIAA0319 is a transmembrane protein associated with dyslexia with a presumed role in neuronal migration. Here we show that KIAA0319 expression is not restricted to the brain but also occurs in sensory and spinal cord neurons, increasing from early postnatal stages to adulthood and being downregulated by injury. This suggested that KIAA0319 participates in functions unrelated to neuronal migration. Supporting this hypothesis, overexpression of KIAA0319 repressed axon growth in hippocampal and dorsal root ganglia neurons; the intracellular domain of KIAA0319 was sufficient to elicit this effect. A similar inhibitory effect was observed in vivo as axon regeneration was impaired after transduction of sensory neurons with KIAA0319. Conversely, the deletion of Kiaa0319 in neurons increased neurite outgrowth in vitro and improved axon regeneration in vivo. At the mechanistic level, KIAA0319 engaged the JAK2-SH2B1 pathway to activate Smad2, which played a central role in KIAA0319-mediated repression of axon growth. In summary, we establish KIAA0319 as a novel player in axon growth and regeneration with the ability to repress the intrinsic growth potential of axons. This study describes a novel regulatory mechanism operating during peripheral nervous system and central nervous system axon growth, and offers novel targets for the development of effective therapies to promote axon regeneration.
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影响因子：
4.5
作者：
Dennis MY;Paracchini S;Scerri TS;Prokunina-Olsson L;Knight JC;Wade-Martins R;Coggill P;Beck S;Green ED;Monaco AP
通讯作者：
Monaco AP
影响因子：
4.1
作者：
Hong, Zebin;Nowakowski, Michal;Jensen, Jan K.
通讯作者：
Jensen, Jan K.
影响因子：
4.3
作者：
Muraki K;Tanigaki K
通讯作者：
Tanigaki K
影响因子：
--
作者：
Maures, Travis J.;Chen, Linyi;Carter-Su, Christin
通讯作者：
Carter-Su, Christin
影响因子：
14.8
作者：
Kaech, Stefanie;Banker, Gary
通讯作者：
Banker, Gary