Department of Physiological Sciences, School of Life Science, The GraduateUniversity for Advanced Studies (SOKENDAI), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
Development. 2012 Mar;139(6):1125-32. doi: 10.1242/dev.069997. Epub 2012 Feb 8.
Sensory neurons possess the central and peripheral branches and they form unique spinal neural circuits with motoneurons during development. Peripheral branches of sensory axons fasciculate with the motor axons that extend toward the peripheral muscles from the central nervous system (CNS), whereas the central branches of proprioceptive sensory neurons directly innervate motoneurons. Although anatomically well documented, the molecular mechanism underlying sensory-motor interaction during neural circuit formation is not fully understood. To investigate the role of motoneuron on sensory neuron development, we analyzed sensory neuron phenotypes in the dorsal root ganglia (DRG) of Olig2 knockout (KO) mouse embryos, which lack motoneurons. We found an increased number of apoptotic cells in the DRG of Olig2 KO embryos at embryonic day (E) 10.5. Furthermore, abnormal axonal projections of sensory neurons were observed in both the peripheral branches at E10.5 and central branches at E15.5. To understand the motoneuron-derived factor that regulates sensory neuron development, we focused on neurotrophin 3 (Ntf3; NT-3), because Ntf3 and its receptors (Trk) are strongly expressed in motoneurons and sensory neurons, respectively. The significance of motoneuron-derived Ntf3 was analyzed using Ntf3 conditional knockout (cKO) embryos, in which we observed increased apoptosis and abnormal projection of the central branch innervating motoneuron, the phenotypes being apparently comparable with that of Olig2 KO embryos. Taken together, we show that the motoneuron is a functional source of Ntf3 and motoneuron-derived Ntf3 is an essential pre-target neurotrophin for survival and axonal projection of sensory neurons.
感觉神经元具有中枢和外周分支，它们在发育过程中与运动神经元形成独特的脊髓神经回路。感觉轴突的外周分支与从中枢神经系统（CNS）延伸到外周肌肉的运动轴突束状聚集，而本体感觉神经元的中枢分支直接支配运动神经元。尽管解剖学上已有充分记录，但在神经回路形成过程中感觉-运动相互作用的分子机制尚未完全了解。为了研究运动神经元对感觉神经元发育的作用，我们分析了 Olig2 敲除（KO）小鼠胚胎背根神经节（DRG）中的感觉神经元表型，该基因敲除的小鼠缺乏运动神经元。我们发现 Olig2 KO 胚胎在胚胎第 10.5 天（E）时 DRG 中的凋亡细胞数量增加。此外，在 E10.5 时观察到感觉神经元的外周分支和 E15.5 时的中枢分支的异常轴突投射。为了了解调节感觉神经元发育的运动神经元衍生因子，我们将重点放在神经营养因子 3（Ntf3；NT-3）上，因为 Ntf3 和其受体（Trk）分别在运动神经元和感觉神经元中强烈表达。使用 Ntf3 条件性敲除（cKO）胚胎分析了运动神经元衍生的 Ntf3 的意义，我们观察到凋亡增加和支配运动神经元的中央分支的异常投射，其表型与 Olig2 KO 胚胎明显相当。总之，我们表明运动神经元是 Ntf3 的功能性来源，而运动神经元衍生的 Ntf3 是感觉神经元存活和轴突投射的必需前靶向神经营养因子。
