MicroRNA-Mediated Non-Cell-Autonomous Regulation of Cortical Radial Glial Transformation Revealed by a Dicer1 Knockout Mouse Model

Radial glia (RG), as neurogenic progenitors and neuronal migration scaffolds, play critical roles during cortical neurogenesis. RG transformation into astrocytes, marking the transition from developmental to physiological function of these cells, is an important step during cortical development. In this study, we aim to determine the roles of microRNAs (miRNAs) during this biological process. In a conditional Dicer1-null mouse where Dicer1 is deleted in both RG and their neuronal progeny, we observe delayed RG transformation as revealed by the persistence of their radial processes, and reduced number and complexity of translocated RG cell bodies in the postnatal cerebral cortex. Downregulation of Notch1 signaling is crucial to RG transformation, and consistently we find that Notch1 signaling is enhanced in the Dicer1-null cerebral cortex. In addition, we show that, among the Notch1 ligands, Jagged2 (Jag2) is preferentially upregulated in the postnatal Dicer1-null cerebral cortex as well as primary embryonic cortical cultures with instant Dicer1 deletion. Functionally, Dicer1-deleted postnatal cerebellar cells with elevated Jag2 expression stimulate a stronger Notch1 signaling in a RG clone L2.3 when co-cultured than control cells. Therefore, we unravel a novel non-cell-autonomous mechanism that regulates RG transformation by modulating Notch1 signaling via miRNA-mediated suppression of the Nocth1 ligand Jag2. Furthermore, we validate Jag2 as a miR-124 target gene and demonstrate in vitro that Jag2 expression is highly sensitive to Dicer1 deletion. Finally, we propose a new concept of MiRNA-Sensitive target genes, identification of which may unravel a unique mode of miRNA-mediated gene expression regulation. GLIA 2015;63:860-876