Data_Sheet_1_Robo2 Receptor Gates the Anatomical Divergence of Neurons Derived From a Common Precursor Origin.pdf

Sensory information relayed to the brain is dependent on complex, yet precise spatial organization of neurons. This anatomical complexity is generated during development from a surprisingly small number of neural stem cell domains. This raises the question of how neurons derived from a common precursor domain respond uniquely to their environment to elaborate correct spatial organization and connectivity. We addressed this question by exploiting genetically labeled mouse embryonic dorsal interneuron 1 (dI1) neurons that are derived from a common precursor domain and give rise to spinal projection neurons with distinct organization of cell bodies with axons projecting either commissurally (dI1c) or ipsilaterally (dI1i). In this study, we examined how the guidance receptor, Robo2, which is a canonical Robo receptor, influenced dI1 guidance during embryonic development. Robo2 was enriched in embryonic dI1i neurons, and loss of Robo2 resulted in misguidance of dI1i axons, whereas dI1c axons remained unperturbed within the mantle zone and ventral commissure. Further, Robo2 profoundly influenced dI1 cell body migration, a feature that was partly dependent on Slit2 signaling. These data suggest that dI1 neurons are dependent on Robo2 for their organization. This work integrated with the field support of a model whereby canonical Robo2 vs. non-canonical Robo3 receptor expression facilitates projection neurons derived from a common precursor domain to read out the tissue environment uniquely giving rise to correct anatomical organization.

传递至大脑的感觉信息，依赖于神经元复杂而精准的空间排布。这类解剖学层面的复杂结构，在个体发育过程中由数量极少的神经干细胞区域分化形成。这引出了一个核心科学问题：源自同一前体区域的神经元，如何通过对所处微环境的差异化响应，构建出正确的空间排布与神经连接。为解答该问题，本研究采用基因标记的小鼠胚胎背侧中间神经元1型（dorsal interneuron 1, dI1）作为模型：该类神经元源自同一前体区域，可分化为两类脊髓投射神经元，其胞体排布存在显著差异，轴突分别向连合侧（dI1c）或同侧（dI1i）投射。本研究聚焦经典Robo家族导向受体Robo2，探究其在胚胎发育阶段对dI1神经元轴突导向的调控作用。实验结果显示，Robo2在胚胎dI1i神经元中呈富集表达状态；敲除Robo2会导致dI1i轴突出现导向错误，而dI1c轴突在套层与腹侧连合中的排布未受明显干扰。此外，Robo2对dI1神经元的胞体迁移具有显著调控作用，这一过程部分依赖于Slit2信号通路。上述实验结果表明，dI1神经元的正常解剖排布依赖于Robo2的功能。结合本领域已有研究成果，本实验结果支持如下模型：经典受体Robo2与非经典受体Robo3的差异化表达，可使源自同一前体区域的投射神经元对组织微环境产生特异性响应，最终形成正确的解剖学排布。