MicroRNA‐mediated non‐cell‐autonomous regulation of cortical radial glial transformation revealed by a Dicer1 knockout mouse model

Abstract

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.

Transformation of the Radial Glia Scaffold Demarcates Two Stages of Human Cerebral Cortex Development

“…Studies in rodents, ferrets, and monkeys have shown that neuronal subtype specification may be determined at the level of radial glia cells, whose competence to produce diverse types of projection neurons becomes progressively restricted during development (Frantz and McConnell, 1996; Lukaszewicz et al, 2005; McConnell, 1988; McConnell and Kaznowski, 1991). In line with this prediction, genetic manipulations that extend radial glia neurogenesis in mouse result in an overproduction of upper cortical layer neurons (Nowakowski et al, 2013; Zhang et al, 2015). To relate the changes in radial glia scaffold organization to changes in the fate of neurons produced, we examined the identity of newborn neurons in the germinal zone using antibodies for the deep (infrangranular) cortical layer neuron markers, TBR1 and CTIP2, and for the marker SATB2, which is highly expressed in upper (supraganular) cortical layers.…”

miR-124 promotes proliferation and differentiation of neuronal stem cells through inactivating Notch pathway

“…Bioinformation prediction showed that Jag1, Jag2 and DLL4 were the potential targets of miR-124. Jag1, Jag2 and Notch down-stream effector Sox9 have been identified as the targets of miR-124 by previous studies [ 14 , 22 – 24 ]. Therefore, our study focused on DLL4 and firstly investigated whether miR-124 could directly target DLL4.…”

Downregulation of miR‐7116‐5p in microglia by MPP+ sensitizes TNF‐α production to induce dopaminergic neuron damage

“…It remains unclear how miR‐7116‐5p in microglia is downregulated. Reported studies have proposed that transcription‐dependent or ‐independent mechanisms are involved in the regulation of miRNA levels (Winter, Jung, Keller, Gregory, & Diederichs, ; Zhang et al, ). Clarifying the mechanism underlying the downregulation of miR‐7116‐5p by MPP + in microglia will help our understanding of the miRNA regulation of TNF‐α production in PD patients.…”