The last common ancestor of Bilateria and Cnidaria is considered to develop a nervous system over 500 million years ago. Despite the long course of evolution, many of the neuron-related genes, which are active in Bilateria, are also found in the cnidarian Hydra. Thus, Hydra is a good model to study the putative primitive nervous system in the last common ancestor that had the great potential to evolve to a more advanced one. Regionalization of the nervous system is one of the advanced features of bilaterian nervous system. Although a regionalized nervous system is already known to be present in Hydra, its developmental mechanisms are poorly understood. In this study we show how it is formed and maintained, focusing on the neuropeptide Hym-176 gene and its paralogs. First, we demonstrate that four axially localized neuron subsets that express different combination of the neuropeptide Hym-176 gene and its paralogs cover almost an entire body, forming a regionalized nervous system in Hydra. Second, we show that positional information governed by the Wnt signaling pathway plays a key role in determining the regional specificity of the neuron subsets as is the case in bilaterians. Finally, we demonstrated two basic mechanisms, regionally restricted new differentiation and phenotypic conversion, both of which are in part conserved in bilaterians, are involved in maintaining boundaries between the neuron subsets. Therefore, this study is the first comprehensive analysis of the anatomy and developmental regulation of the divergently evolved and axially regionalized peptidergic nervous system in Hydra, implicating an ancestral origin of neural regionalization.

Bilateria和Cnidaria的最后共同祖先被认为在5亿年前发展了神经系统。尽管进化的过程很长，但在刺蛇蛇的九头蛇中也发现了许多与神经元有关的基因，这些基因在Bilateria中有活性。因此，Hydra是研究假定的原始神经系统的一个很好的模型，该系统在最后一个祖先中具有很大的潜力，可以进化到更高级的祖先。神经系统的区域化是双边神经系统的高级特征之一。尽管已知九头蛇中存在区域性神经系统，其发展机制了解甚少。在这项研究中，我们重点介绍了神经肽Hym-176基因及其旁系同源物，说明了它是如何形成和维持的。首先，我们证明了表达神经肽Hym-176基因及其旁系同源物不同组合的四个轴向局部神经元子集几乎覆盖了整个身体，在Hydra中形成了区域神经系统。其次，我们证明了由Wnt信号通路控制的位置信息在确定神经元子集的区域特异性中起着关键作用，就像在双语者中一样。最后，我们证明了两种基本机制，即区域限制的新分化和表型转化，这两种机制在部分双语者中都得到了保留，它们参与了维持神经元子集之间的界限。因此，本研究是对九头蛇的不同进化和轴向区域化的肽能神经系统进行解剖学和发育调控的首次综合分析，暗示了神经区域化的祖先。