Repression of Irs2 by let‐7 miRNAs is essential for homeostasis of the telencephalic neuroepithelium.

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 studied the role of microRNAs in the embryonic telencephalon as key regulators of gene expression. By using the early recombiner Rx‐Cre mouse, we identify novel and critical roles of miRNAs in early brain development, demonstrating they are essential to preserve the cellular homeostasis and structural integrity of the telencephalic neuroepithelium. We show that Rx‐Cre;DicerF/F mouse embryos have a severe disruption of the telencephalic apical junction belt, followed by invagination of the ventricular surface and formation of hyperproliferative rosettes. Transcriptome 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. Synopsis: Dicer1‐dependent let‐7 microRNAs are critical to repress p53 pathway activity and Irs2 expression levels in the early telencephalic neuroepithelium, which otherwise enters into hyperproliferation and loss of adhesion of progenitor cells, leading to the formation of true rosettes reminiscent of pediatric cancers. Loss of miRNAs in the early embryonic telencephalon of Rx‐Cre;Dicer1flox mutant mice produces massive transient apoptosis of progenitor cells, loss of adherens junctions and increased proliferation, leading to the formation of true hyperproliferative rosettes.Rx‐Dicer mutants have a significant loss of let‐7 family microRNAs, and increased p53 signaling and Irs2 expression. Loss of p53 in Rx‐Dicer mutants rescues their phenotype in a partially‐penetrant manner.Increased Irs2 expression or blockade of let‐7 activity in early wild‐type embryos, induce rosette formation in the rostral telencephalon, rescued by overexpression of let‐7 and downregulation of Irs‐2, respectively.Let‐7 miRNAs downregulate the amplification of human cortical progenitor cells by repressing Irs2 expression, consistent with a role of this signaling axis in pediatric cancers with true rosettes. [ABSTRACT FROM AUTHOR]