title: MicroRNAs establish robustness and adaptability of a critical gene network to regulate progenitor fate decisions during cortical neurogenesis.
abstract: Over the course of cortical neurogenesis, the transition of progenitors from proliferation to differentiation requires a precise regulation of involved gene networks under varying environmental conditions. In order to identify such regulatory mechanisms, we analyzed microRNA (miRNA) target networks in progenitors during early and late stages of neurogenesis. We found that cyclin D1 is a network hub whose expression is miRNA-dosage sensitive. Experimental validation revealed a feedback regulation between cyclin D1 and its regulating miRNAs miR-20a, miR-20b, and miR-23a. Cyclin D1 induces expression of miR-20a and miR-20b, whereas it represses miR-23a. Inhibition of any of these miRNAs increases the developmental stage-specific mean and dynamic expression range (variance) of cyclin D1 protein in progenitors, leading to reduced neuronal differentiation. Thus, miRNAs establish robustness and stage-specific adaptability to a critical dosage-sensitive gene network during cortical neurogenesis. Understanding such network regulatory mechanisms for key developmental events can provide insights into individual susceptibilities for genetically complex neuropsychiatric disorders.
authors.affiliation: Inserm, UMR-S839, Paris 75005, France; Sorbonne Universités, UPMC Université Paris 06, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, France.
authors.forename: Tanay
authors.initials: T
authors.lastname: Ghosh
authors.affiliation: Center for Regenerative Therapies, TU-Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Julieta
authors.initials: J
authors.lastname: Aprea
authors.affiliation: Inserm, U1141, Paris, 75019, France; Université Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris 75019, France.
authors.forename: Jeannette
authors.initials: J
authors.lastname: Nardelli
authors.affiliation: Renal Department, University Medical Center, Breisacher Strasse 66, Freiburg 79106, Germany.
authors.forename: Hannes
authors.initials: H
authors.lastname: Engel
authors.affiliation: Department of Microbiology, School of Medicine, University of Washington, Seattle, WA 98195-8070, USA.
authors.forename: Christian
authors.initials: C
authors.lastname: Selinger
authors.affiliation: Inserm, UMR-S839, Paris 75005, France; Sorbonne Universités, UPMC Université Paris 06, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, France.
authors.forename: Cedric
authors.initials: C
authors.lastname: Mombereau
authors.affiliation: Inserm, UMR-S839, Paris 75005, France; Sorbonne Universités, UPMC Université Paris 06, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, France.
authors.forename: Thomas
authors.initials: T
authors.lastname: Lemonnier
authors.affiliation: Inserm, UMR-S839, Paris 75005, France; Sorbonne Universités, UPMC Université Paris 06, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, France.
authors.forename: Imane
authors.initials: I
authors.lastname: Moutkine
authors.affiliation: Inserm, U1141, Paris, 75019, France; Université Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris 75019, France.
authors.forename: Leslie
authors.initials: L
authors.lastname: Schwendimann
authors.affiliation: Center for Regenerative Therapies, TU-Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Martina
authors.initials: M
authors.lastname: Dori
authors.affiliation: Inserm, UMR-S839, Paris 75005, France; Sorbonne Universités, UPMC Université Paris 06, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, France.
authors.forename: Theano
authors.initials: T
authors.lastname: Irinopoulou
authors.affiliation: Inserm, UMR1163, GenAtlas, Institute Imagine, Université Paris Descartes, Paris 75015, France.
authors.forename: Alexandra
authors.initials: A
authors.lastname: Henrion-Caude
authors.affiliation: Institut des Hautes Etudes Scientifiques, Bures sur Yvette 91440, France; CNRS UMR 7224, Université Pierre and Marie Curie, Paris 75005, France.
authors.forename: Arndt G
authors.initials: AG
authors.lastname: Benecke
authors.affiliation: Renal Department, University Medical Center, Breisacher Strasse 66, Freiburg 79106, Germany; BIOSS Centre of Biological Signalling Studies, Albert-Ludwigs-University, Freiburg 79085, Germany.
authors.forename: Sebastian J
authors.initials: SJ
authors.lastname: Arnold
authors.affiliation: Inserm, U1141, Paris, 75019, France; Université Paris Diderot, Sorbonne Paris Cité, UMRS 1141, Paris 75019, France; Centre for the Developing Brain, King's College, St Thomas' Campus, WC2R2LS London, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Gressens
authors.affiliation: Center for Regenerative Therapies, TU-Dresden, Fetscherstraße 105, 01307 Dresden, Germany.
authors.forename: Federico
authors.initials: F
authors.lastname: Calegari
authors.affiliation: Inserm, UMR-S839, Paris 75005, France; Sorbonne Universités, UPMC Université Paris 06, Paris 75005, France; Institut du Fer à Moulin, Paris 75005, France. Electronic address: matthias.groszer@inserm.fr.
authors.forename: Matthias
authors.initials: M
authors.lastname: Groszer
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics*; D055495:Neurogenesis / Q000235:genetics*; D013234:Stem Cells / Q000166:cytology*
chemical_list: D035683:MicroRNAs