Tseng Ching-San, Zhuang Zi-Hui, Hsing Hsiang-Wei, Lee Chia-Ming, Hsu Tsan-Ting, Pan Yu-Kuan, Hsueh Yi-Ping, Chen Bi-Chang, Chou Shen-Ju
Institute of Cellular and Organismic Biology, Academia Sinica, Taipei, Taiwan.
Department of Anatomy, School of Medicine, China Medical University, Taichung, Taiwan.
PLoS Biol. 2025 Aug 25;23(8):e3003355. doi: 10.1371/journal.pbio.3003355. eCollection 2025 Aug.
The hippocampus is a key brain region for learning and memory that can be divided into multiple compartments, including the dorsal and ventral hippocampi. Each compartment has unique functions, connectivity, and molecular properties. However, the molecular mechanisms underlying the specification of these subregions remain unclear. In this study, we investigated the role of COUP-TFI, a patterning transcription factor expressed in a high-caudal-to-low-rostral gradient in hippocampal progenitors, in establishing the dorsal-ventral axis of the hippocampus in mice. The highest COUP-TFI expression in the hippocampal progenitors was observed in the caudal medial pallium that gives rise to the ventral hippocampus, and the lowest expression was found in rostral medial pallium that develops into the dorsal hippocampus. We generated mice with different levels of COUP-TFI expression in the cortex and performed a comprehensive analysis of subregion-specific gene expression across the entire hippocampus in these mice. The deletion of COUP-TFI resulted in an expansion of the dorsal hippocampus at the expense of the ventral hippocampus. Conversely, increased COUP-TFI expression led to the generation of ectopic ventral hippocampus in the dorsal compartments. We further demonstrated that COUP-TFI dose-dependently regulates Wnt signaling pathway, a crucial player in regulating hippocampus development. Together, our findings reveal a novel mechanism governing hippocampal development, in which COUP-TFI determines the fate of hippocampal subregions and balances the hippocampus into dorsal and ventral compartments.
海马体是学习和记忆的关键脑区，可分为多个部分，包括背侧和腹侧海马体。每个部分都有独特的功能、连接性和分子特性。然而，这些亚区域特化的分子机制仍不清楚。在本研究中，我们调查了COUP-TFI的作用，它是一种在海马祖细胞中以高尾端到低嘴端梯度表达的模式转录因子，在建立小鼠海马体的背腹轴中发挥作用。在产生腹侧海马体的尾侧内侧皮质中观察到海马祖细胞中COUP-TFI的最高表达，而在发育成背侧海马体的嘴侧内侧皮质中发现最低表达。我们在皮质中产生了具有不同水平COUP-TFI表达的小鼠，并对这些小鼠整个海马体中特定亚区域的基因表达进行了全面分析。COUP-TFI的缺失导致背侧海马体扩张，腹侧海马体减少。相反，COUP-TFI表达增加导致背侧部分出现异位腹侧海马体。我们进一步证明，COUP-TFI以剂量依赖的方式调节Wnt信号通路，Wnt信号通路是调节海马体发育的关键因子。总之，我们的研究结果揭示了一种控制海马体发育的新机制，其中COUP-TFI决定海马体亚区域的命运，并将海马体平衡为背侧和腹侧部分。
