title: MicroRNA-34/449 controls mitotic spindle orientation during mammalian cortex development.
abstract: Correct orientation of the mitotic spindle determines the plane of cellular cleavage and is crucial for organ development. In the developing cerebral cortex, spindle orientation defects result in severe neurodevelopmental disorders, but the precise mechanisms that control this important event are not fully understood. Here, we use a combination of high-content screening and mouse genetics to identify the miR-34/449 family as key regulators of mitotic spindle orientation in the developing cerebral cortex. By screening through all cortically expressed miRNAs in HeLa cells, we show that several members of the miR-34/449 family control mitotic duration and spindle rotation. Analysis of miR-34/449 knockout (KO) mouse embryos demonstrates significant spindle misorientation phenotypes in cortical progenitors, resulting in an excess of radial glia cells at the expense of intermediate progenitors and a significant delay in neurogenesis. We identify the junction adhesion molecule-A (JAM-A) as a key target for miR-34/449 in the developing cortex that might be responsible for those defects. Our data indicate that miRNA-dependent regulation of mitotic spindle orientation is crucial for cell fate specification during mammalian neurogenesis.
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) Vienna Biocenter (VBC), Vienna, Austria jpfededa@gmail.com daniel.gerlich@imba.oeaw.ac.at.
authors.forename: Juan Pablo
authors.initials: JP
authors.lastname: Fededa
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Christopher
authors.initials: C
authors.lastname: Esk
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Beata
authors.initials: B
authors.lastname: Mierzwa
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Rugile
authors.initials: R
authors.lastname: Stanyte
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA.
authors.forename: Shuiqiao
authors.initials: S
authors.lastname: Yuan
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA.
authors.forename: Huili
authors.initials: H
authors.lastname: Zheng
authors.affiliation: Institute-associated Research Group "Cell Adhesion and Cell Polarity", Institute of Medical Biochemistry, ZMBE, Münster, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Ebnet
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, Reno, NV, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) Vienna Biocenter (VBC), Vienna, Austria.
authors.forename: Juergen A
authors.initials: JA
authors.lastname: Knoblich
authors.affiliation: Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA) Vienna Biocenter (VBC), Vienna, Austria jpfededa@gmail.com daniel.gerlich@imba.oeaw.ac.at.
authors.forename: Daniel W
authors.identifier: 0000-0003-1637-3365
authors.initials: DW
authors.lastname: Gerlich
mesh_terms: D000818:Animals; D002540:Cerebral Cortex / Q000196:embryology*; D006367:HeLa Cells; D006801:Humans; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000378:metabolism*; D008941:Spindle Apparatus / Q000378:metabolism*
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; C538721:Mirn449 microRNA, mouse
keywords: cortex development; miR‐449; neurogenesis; radial glia; spindle orientation