Department of Anatomy and Neuroscience, Graduate School of Medicine, Osaka University, Osaka 565-0871, Japan.
Division of Cell Biology and Neuroscience, Department of Morphological and Physiological Sciences, Faculty of Medical Sciences, University of Fukui, Fukui 910-1193, Japan.
J Neurosci. 2021 Jun 2;41(22):4795-4808. doi: 10.1523/JNEUROSCI.0367-20.2021. Epub 2021 Apr 27.
Coordination of skilled movements and motor planning relies on the formation of regionally restricted brain circuits that connect cortex with subcortical areas during embryonic development. Layer 5 neurons that are distributed across most cortical areas innervate the pontine nuclei (basilar pons) by protrusion and extension of collateral branches interstitially along their corticospinal extending axons. Pons-derived chemotropic cues are known to attract extending axons, but molecules that regulate collateral extension to create regionally segregated targeting patterns have not been identified. Here, we discovered that and are expressed in the cortex and the basilar pons in a region-specific and mutually exclusive manner, and that their repulsive activities are essential for segregating collateral extensions from corticospinal axonal tracts in mice. Specifically, and forward and reverse inhibitory signals direct collateral extension such that -positive frontal and occipital cortical areas extend their axon collaterals into the -negative rostral part of the basilar pons, whereas -positive parietal cortical areas extend their collaterals into the -negative caudal part of the basilar pons. Together, our results provide a molecular basis that explains how the corticopontine projection connects multimodal cortical outputs to their subcortical targets. Our findings put forward a model in which region-to-region connections between cortex and subcortical areas are shaped by mutually exclusive molecules to ensure the fidelity of regionally restricted circuitry. This model is distinct from earlier work showing that neuronal circuits within individual cortical modalities form in a topographical manner controlled by a gradient of axon guidance molecules. The principle that a shared molecular program of mutually repulsive signaling instructs regional organization-both within each brain region and between connected brain regions-may well be applicable to other contexts in which information is sorted by converging and diverging neuronal circuits.
协调熟练运动和运动规划依赖于胚胎发育过程中形成的区域性限制的大脑回路，这些回路将皮层与皮质下区域连接起来。分布在大多数皮层区域的第 5 层神经元通过沿着皮质脊髓延伸轴突的侧支分支的突起和延伸来支配桥脑核（基底脑桥）。已知桥脑衍生的趋化线索吸引延伸轴突，但调节侧支延伸以创建区域性隔离靶向模式的分子尚未被鉴定。在这里，我们发现 和 在皮层和基底脑桥中以区域特异性和相互排斥的方式表达，并且它们的排斥活性对于在小鼠中分离皮质脊髓延伸轴突束中的侧支延伸是必不可少的。具体而言， 和 向前和反向抑制信号指导侧支延伸，使得 阳性额和枕叶皮层区域将其轴突侧支延伸到 阴性基底脑桥的前颅部分，而 阳性顶叶皮层区域将其侧支延伸到 阴性基底脑桥的尾侧部分。总之，我们的结果提供了一个分子基础，解释了皮质桥脑投射如何将多模态皮质输出连接到其皮质下靶标。我们的发现提出了一个模型，即皮质和皮质下区域之间的区域间连接是由相互排斥的分子形成的，以确保区域性限制回路的保真度。该模型与早期工作不同，早期工作表明，单个皮质模态内的神经元回路以受轴突导向分子梯度控制的拓扑方式形成。共享相互排斥信号的分子程序指导区域组织的原则-无论是在每个脑区内部还是在连接的脑区之间-可能适用于其他情况下，信息通过汇聚和发散的神经元回路进行分类。
