title: MicroRNA-independent functions of DGCR8 are essential for neocortical development and TBR1 expression.
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 conditionalDgcr8andDicerknockout mice, we show thatDgcr8deletion, in contrast toDicerdepletion, 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 thatDgcr8mutations induce an earlier and stronger phenotype in the developing nervous system compared toDicermutants 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 theTbr1transcript, containing evolutionarily conserved hairpins that resemble miRNA precursors, independently of miRNAs.
authors.affiliation: Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Federica
authors.initials: F
authors.lastname: Marinaro
authors.affiliation: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Matteo J
authors.initials: MJ
authors.lastname: Marzi
authors.affiliation: Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Nadin
authors.initials: N
authors.lastname: Hoffmann
authors.affiliation: Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Hayder
authors.initials: H
authors.lastname: Amin
authors.affiliation: Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Roberta
authors.initials: R
authors.lastname: Pelizzoli
authors.affiliation: Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Niola
authors.affiliation: Center for Genomic Science of IIT@SEMM, Istituto Italiano di Tecnologia, Milan, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Nicassio
authors.affiliation: Neuroscience and Brain Technologies Department, Istituto Italiano di Tecnologia, Genoa, Italy davide.depietri@iit.it.
authors.forename: Davide
authors.identifier: 0000-0001-9537-8900
authors.initials: D
authors.lastname: De Pietri Tonelli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D051792:Basic Helix-Loop-Helix Proteins; D002460:Cell Line; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D017353:Gene Deletion; D018507:Gene Expression Regulation, Developmental; D018398:Homeodomain Proteins / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D019579:Neocortex / Q000196:embryology* / Q000378:metabolism* / Q000473:pathology; D009419:Nerve Tissue Proteins; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis / Q000235:genetics; D009474:Neurons / Q000378:metabolism; D034622:RNA Interference; D016601:RNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D020825:T-Box Domain Proteins; D014157:Transcription Factors / Q000378:metabolism; D000099260:Empty Spiracles Homeobox Proteins
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D004268:DNA-Binding Proteins; D018398:Homeodomain Proteins; D035683:MicroRNAs; D009419:Nerve Tissue Proteins; D016601:RNA-Binding Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D000099260:Empty Spiracles Homeobox Proteins; C474044:Dgcr8 protein, mouse; C102938:Neurog2 protein, mouse; C492271:Tbr1 protein, mouse
keywords: Dgcr8; Tbr1; microRNAs; murine corticogenesis; neurogenesis