Repression of Irs2 by let-7 miRNAs is essential for the homeostasis of the telencephalic neuroepithelium [RNA-seq]
The structural integrity and cellular homeostasis of the embryonic stem cell niche are critical for normal tissue development. In the telencephalic neuroepithelium, this is controlled in part by cell adhesion molecules and regulators of progenitor cell lineage, but the specific orchestration of these processes remains unknown. Here we have studied the role of microRNAs in the embryonic telencephalon as key regulators of gene expression. By using the early recombiner Rx-Cre mouse, we demonstrate that miRNAs are essential to preserve the cellular homeostasis and structural integrity of the telencephalic neuroepithelium. We show that Rx-Cre;Dicerflox/flox mouse embryos have a severe disruption of the telencephalic apical junction belt, followed by invagination of the ventricular surface and formation of hyperproliferative rosettes. Transcriptomic analyses and functional experiments in vivo show that these defects result from upregulation of Irs2 upon loss of let-7 miRNAs, in an apoptosis-independent manner. Our results reveal an unprecedented relevance of miRNAs in early forebrain development, with potential mechanistic implications in pediatric brain cancer. Overall design: The rostral-most region of the telencephalic primordium was dissected out from DicerF/F and RxCre-DicerF/F E11.5 embryos, and miRNA expression profiles were analysed by RNA sequencing (RNA-seq).