Back-signaling from CX3CL1 regulates neurogenesis during development and in the adult mouse

CX3CL1 was discovered as a chemokine, and is best known to function via interaction with its receptor CX3CR1. However, in this study, we report a unique role of CX3CL1 that is independent from this pathway. We show that CX3CL1 is naturally shedded by both α- and β-secretase. The membrane-anchored C-terminal fragment is further cleaved by γ-secretase to release the CX3CL1 intracellular domain (CX3CL1-ICD), which is translocated into the cell nucleus to control gene expression. Among the regulated genes, we noted prominent induction of TGFβ2/TGFβ3 signaling in cultured cells by CX3CL1-ICD. Mice overexpressing only the C-terminal fragment (Tg-CX3CL1-ct) strongly induced TGFβ3 expression, as evidenced by Western and RNAseq analyses. Phenotypically, Tg-CX3CL1-ct mice exhibited enhanced neurogenesis both during development and in adulthood. Enhanced adult neurogenesis was seen in both the subgranular zone and the subventricular zone. Together, we demonstrate that CX3CL1-ct has a back-signaling function by enhancing neurogenesis through TGFβ3 and other genes important for neurogenesis. Induction CX3CL1 back signaling may be a promising novel mechanism to replenish neuronal loss. NGS RNA-Seq profiling of P0 mouse hippocampi