MicroRNA‐independent functions of DGCR8 are essential for neocortical development and TBR1 expression. (23rd February 2017)

• Record Type: Journal Article
• Authors: Marinaro, Federica; Marzi, Matteo J; Hoffmann, Nadin; Amin, Hayder; Pelizzoli, Roberta; Niola, Francesco; Nicassio, Francesco; De Pietri Tonelli, Davide
• Is Part Of: EMBO reports. Volume 18:Number 4(2017)
• Page Start: 603
• Page End: 618
• Publication Date: 2017-02-23
• Subjects: Dgcr8 -- microRNAs -- murine corticogenesis -- neurogenesis -- Tbr1; Molecular biology -- Periodicals; Molecular Biology -- Periodicals; Molecular biology; Periodicals; 572.8
• DOI: 10.15252/embr.201642800
• Languages: English
• ISSNs: 1469-221X

Abstract

Abstract: Recent evidence indicates that the miRNA biogenesis factors DROSHA, DGCR8, and DICER exert non‐overlapping functions, and have also roles in miRNA‐independent regulatory mechanisms. However, it is currently unknown whether miRNA‐independent functions of DGCR8 play any role in the maintenance of neuronal progenitors and during corticogenesis. Here, by phenotypic comparison of cortices from conditional Dgcr8 and Dicer knockout mice, we show that Dgcr8 deletion, in contrast to Dicer depletion, leads to premature differentiation of neural progenitor cells and overproduction of TBR1‐positive neurons. Remarkably, depletion of miRNAs upon DCGR8 loss is reduced compared to DICER loss, indicating that these phenotypic differences are mediated by miRNA‐independent functions of DGCR8. We show that Dgcr8 mutations induce an earlier and stronger phenotype in the developing nervous system compared to Dicer mutants and that miRNA‐independent functions of DGCR8 are critical for corticogenesis. Finally, our data also suggest that the Microprocessor complex, with DROSHA and DGCR8 as core components, directly regulates the Tbr1 transcript, containing evolutionarily conserved hairpins that resemble miRNA precursors, independently of miRNAs. Synopsis: DGCR8 and DICER are required for canonical miRNA biogenesis. This study describes miRNA‐independent roles of DGCR8 that control progenitor cell expansion and neurogenesis, and promote targeting of the mRNA of the cortical transcription factor Tbr1. Dgcr8 loss induces more severe cortical alterations as Dicer depletion, premature differentiation of basal progenitors, and the overproduction of TBR1 + neurons. Depletion of miRNAs upon DCGR8 loss is reduced compared to DICER deficiency, revealing novel non‐canonical miRNAs in corticogenesis. DGCR8 controls Tbr1 expression post‐transcriptionally and independently of miRNAs. The DGCR8/DROSHA Microprocessor complex cleaves evolutionary conserved hairpins in the Tbr1 transcript. Abstract : DGCR8 and DICER are required for canonical miRNA biogenesis. This study describes miRNA‐independent roles of DGCR8 that control progenitor cell expansion and neurogenesis, and promote targeting of the mRNA of the cortical transcription factor Tbr1.