The Role and Relationship of S1P and Reelin in the Horizontal-to-Radial Transitioning of Newly Generated DGCs in the Hippocampus

The radial-to-horizontal positioning of newborn dentate granule cells (DGCs) is a crucial step in adult hippocampal neurogenesis, yet the molecular machinery governing this process remains largely obscure. Two extracellular proteins, sphingosine-1-phosphate (S1P) and Reelin, are implicated independently from each other in cell migration and differentiation. However, whether these proteins act cooperatively to accomplish DGC repositioning has not been established. This study aims to examine the interaction between S1P and Reelin during horizontal-to-radial transitioning and whether Reelin modulates S1P signaling. To address this question, RNA sequencing, antibody staining and retroviral knockdowns were used to identify the sites of S1P production and assess the effects of S1P and Reelin deficiency on DGC migration. Our results show that both proteins are required for proper transitioning, as knockdown of either S1P or Reelin leads to loss of radial orientation, reduced dendrite growth, and impaired synaptic activity. Furthermore, our findings suggest that Reelin functions upstream of S1P signaling, uncovering a cooperative action between them in DGC repositioning. By elucidating the roles of S1P and Reelin in neurogenesis through these findings not only gives us a better understanding of hippocampal circuit integration but also open insights into possible therapeutic targets in diseases with impaired neurogenesis, such as cognitive decline and neurodegenerative diseases.