The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
The Wolfson Centre for Age-Related Diseases, King's College London, Guy's Campus, London SE1 1UL, United Kingdom.
Neurobiol Dis. 2018 Mar;111:70-79. doi: 10.1016/j.nbd.2017.12.016. Epub 2017 Dec 20.
Stimulation of retinoic acid (RA) mediated signalling pathways following neural injury leads to regeneration in the adult nervous system and numerous studies have shown that the specific activation of the retinoic acid receptor β (RARβ) is required for this process. Here we identify a novel mechanism by which neuronal RARβ activation results in the endogenous synthesis of RA which is released in association with exosomes and acts as a positive cue to axonal/neurite outgrowth. Using an established rodent model of RARβ induced axonal regeneration, we show that neuronal RARβ activation upregulates the enzymes involved in RA synthesis in a cell specific manner; alcohol dehydrogenase7 (ADH7) in neurons and aldehyde dehydrogenase 2 (Raldh2) in NG2 expressing cells (NG2+ cells). These release RA in association with exosomes providing a permissive substrate to neurite outgrowth. Conversely, deletion of Raldh2 in the NG2+ cells in our in vivo regeneration model is sufficient to compromise axonal outgrowth. This hitherto unidentified RA paracrine signalling is required for axonal/neurite outgrowth and is initiated by the activation of neuronal RARβ signalling.
神经损伤后，视黄酸（RA）介导的信号通路的刺激会导致成年神经系统的再生，许多研究表明，RA 受体 β（RARβ）的特异性激活是这一过程所必需的。在这里，我们确定了一种新的机制，即神经元 RARβ 的激活导致内源性 RA 的合成，RA 与外泌体一起释放，并作为轴突/神经突生长的正趋化因子。我们使用 RARβ 诱导的轴突再生的成熟啮齿动物模型表明，神经元 RARβ 的激活以细胞特异性的方式上调 RA 合成相关的酶；在神经元中是醇脱氢酶 7（ADH7），在 NG2 表达细胞（NG2+细胞）中是醛脱氢酶 2（Raldh2）。这些酶与外泌体一起释放 RA，为神经突生长提供了一个许可的基质。相反，在我们的体内再生模型中，NG2+细胞中 Raldh2 的缺失足以损害轴突的生长。这种迄今为止尚未被识别的 RA 旁分泌信号对于轴突/神经突的生长是必需的，并且是由神经元 RARβ 信号的激活所引发的。
