Repression of Irs2 by let‐7 mi RNA s is essential for homeostasis of the telencephalic neuroepithelium

Abstract

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 micro RNA s 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 mi RNA s 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;Dicer F / 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 mi RNA s in an apoptosis‐independent manner. Our results reveal an unprecedented relevance of mi RNA s in early forebrain development, with potential mechanistic implications in pediatric brain cancer.

MicroRNAs Instruct and Maintain Cell Type Diversity in the Nervous System

“…However, miRNAs may persist long after DICER knockout begins, meaning that this manipulation may not effectively probe miRNA function in early progenitors. miRNA ablation at an earlier timepoint—using Rx-Cre-driven conditional knockout of DICER, which starts at E7.5—caused overt structural defects in the neuroepithelium by disrupting adherens junctions and inducing hyperproliferation of radial glial cells ( Fernández et al, 2020 ). Part of the above phenotype seem to be mediated by miR-302a-d, a member of a miRNA family highly implicated in regulating cell cycle in embryonic stem cells.…”

MiRNAs in early brain development and pediatric cancer

“…Altogether, this study reveals the existence of key periods of development when neural progenitors are highly sensitive to miRNA dysregulation, possibly leading to the initiation of major brain pathologies. [ 68 ]…”

“…[ 88 ] In a recent study, our laboratory revealed that loss of let‐7 miRNAs in the early embryonic forebrain (by means of Rx ‐dependent conditional Dicer1 KO) upregulates multiple signaling pathways that promote cell proliferation and loss of apical cell adhesion, resulting in the critical loss of homeostasis of the telencephalic neuroepithelium. [ 68 ] Let‐7 miRNA synthesis is subject to post‐transcriptional mechanisms of regulation, controlling the accumulation of mature miRNAs. [ 89 ] One of these regulatory mechanisms is a double‐negative feedback loop between let‐7 and the pluripotency factor Lin28.…”

“…Contrary to previous Dicer1 conditional mutant mouse lines, recombining at later stages, this very early mutation results in a dramatic increase in aRCG proliferation and loss of the apical AJ belt, leading to the formation of hyperproliferative rosettes with histological resemblance to ETMR tumors. [ 68 ] At the transcriptomic level, the early loss of Dicer1 leads to a specific decrease of let‐7 miRNA expression in the early rostral telencephalon, which results in the derepression of Irs2 and several components of the TP53 signaling pathway. [ 68 ] The resulting increased activity of TP53 signaling leads to augmented apoptosis early in development, which combined with reduced let‐7 levels, significantly increases Irs2 expression.…”

LncRNA SNHG11 Promotes Temozolomide Resistance in Glioblastoma via Promoting MGMT Expression

“…IRS2 could also be regulated by ncRNAs, like miRNAs. For example, IRS2 is a direct target of let-7 miRNA, and let-7/IRS2 is essential for the telencephalic neuroepithelium 27 . Here, we identi ed that IRS2 is also a direct target of miR-7-5p.…”