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

Virginia Fernández,Rafael Soler,Ugo Tomasello,Maria Ángeles Martínez‐Martínez,Yuki Nomura,Anna Prieto‐Colomina,José P López‐Atalaya,Martina Dori,Federico Calegari,Víctor Borrell,Adrián Cárdenas

doi:10.15252/embj.2020105479

Virginia Fernández, Rafael Soler + Show 9 more

Open Access

https://doi.org/10.15252/embj.2020105479

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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 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;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 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.

Highlights

The development of the telencephalon is a highly complex process involving a sequence of key events
These analyses showed that Cre recombination in Rx-Cre mouse embryos is most prevalent in the rostral and ventral telencephalon at E11.5 and E12.5, while it is significantly lower in the neocortex, in its medial and caudal aspects
Our results demonstrated that the loss of cellular homeostasis and formation of rosettes in the telencephalic neuroepithelium require high levels of insulin receptor substrate-2 (Irs2), but not massive apoptosis, supporting the notion that this phenotype in Rx-Dicer mutants emerges from their increased Irs2 levels

Summary

Introduction

The development of the telencephalon is a highly complex process involving a sequence of key events. ARGCs are highly polarized and extend thin processes attached to the ventricular (apical) and pial (basal) surfaces of the developing telencephalon, with the cell bodies forming the ventricular zone (VZ). Their apical process terminates at the ventricular surface in an end foot, which serves to anchor aRGCs to each other via adherens junctions. This maintains the polarity of aRGCs and the cellular homeostasis and structural integrity of the VZ (Gotz & Huttner, 2005; Marthiens et al, 2010). Most basal progenitors are intermediate progenitor cells (IPCs), producing the majority of excitatory neurons (Haubensak et al, 2004; Kowalczyk et al, 2009; Taverna et al, 2014)

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