A developmental gradient of COUP-TFI expression regulates the relative size of hippocampus dorsal and ventral subregions

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.