The hippocampus has an orderly and layered structure. Pyramidal neurons and dentate granule cells must migrate correctly for the formation of the layer structure of the hippocampus. In human, abnormal structure of hippocampus is implicated in neurological disorders.
Reelin is a large secreted glycoprotein that is required for normal brain formation. However, the role of Reelin in the developing brain and its underlying regulatory molecular mechanism are not fully understood. Reelin protein is composed of the N-terminal domain, Reelin repeats, and the highly basic C-terminal region (CTR). The primary sequence of CTR is conserved in most vertebrates, suggesting its important functions.
We previously found that CTR is important for efficient activation of Reelin downstream signaling in vitro. In this study, to clarify the CTR-dependent function in vivo, we generated a knock-in mouse lacking CTR and analyzed the structure of hippocampus. In this knock-in mouse, the hippocampal CA3 region was normally formed while CA1 region was split into two layers, and the dentate granule cell layer was less packed. In order to elucidate the mechanism of CTR-dependent signaling, we utilized alkaline phosphatase (AP) fused Reelin. AP-fused Reelin with CTR, but not one without CTR, bound to a molecule that was expressed in CA1 neurons. These results suggest that the CTR-dependent signaling is required for normal formation of CA1 through an unidentified receptor.