title: A unilateral negative feedback loop between miR-200 microRNAs and Sox2/E2F3 controls neural progenitor cell-cycle exit and differentiation.
abstract: MicroRNAs have emerged as key posttranscriptional regulators of gene expression during vertebrate development. We show that the miR-200 family plays a crucial role for the proper generation and survival of ventral neuronal populations in the murine midbrain/hindbrain region, including midbrain dopaminergic neurons, by directly targeting the pluripotency factor Sox2 and the cell-cycle regulator E2F3 in neural stem/progenitor cells. The lack of a negative regulation of Sox2 and E2F3 by miR-200 in conditional Dicer1 mutants (En1(+/Cre); Dicer1(flox/flox) mice) and after miR-200 knockdown in vitro leads to a strongly reduced cell-cycle exit and neuronal differentiation of ventral midbrain/hindbrain (vMH) neural progenitors, whereas the opposite effect is seen after miR-200 overexpression in primary vMH cells. Expression of miR-200 is in turn directly regulated by Sox2 and E2F3, thereby establishing a unilateral negative feedback loop required for the cell-cycle exit and neuronal differentiation of neural stem/progenitor cells. Our findings suggest that the posttranscriptional regulation of Sox2 and E2F3 by miR-200 family members might be a general mechanism to control the transition from a pluripotent/multipotent stem/progenitor cell to a postmitotic and more differentiated cell.
authors.affiliation: Institute of Developmental Genetics, Helmholtz Zentrum München, Deutsches Forschungszentrum für Umwelt und Gesundheit, and Technische Universität München-Weihenstephan, D-85764 Neuherberg, Germany.
authors.forename: Changgeng
authors.initials: C
authors.lastname: Peng
authors.forename: Na
authors.initials: N
authors.lastname: Li
authors.forename: Yen-Kar
authors.initials: YK
authors.lastname: Ng
authors.forename: Jingzhong
authors.initials: J
authors.lastname: Zhang
authors.forename: Florian
authors.initials: F
authors.lastname: Meier
authors.forename: Fabian J
authors.initials: FJ
authors.lastname: Theis
authors.forename: Matthias
authors.initials: M
authors.lastname: Merkenschlager
authors.forename: Wei
authors.initials: W
authors.lastname: Chen
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Wurst
authors.forename: Nilima
authors.initials: N
authors.lastname: Prakash
mesh_terms: D000367:Age Factors; D000818:Animals; D002452:Cell Count; D002453:Cell Cycle / Q000235:genetics / Q000502:physiology*; D016923:Cell Death / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology*; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000378:metabolism; D050699:E2F3 Transcription Factor / Q000235:genetics / Q000378:metabolism*; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000235:genetics / Q000502:physiology*; D049452:Green Fluorescent Proteins / Q000235:genetics; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D008297:Male; D008636:Mesencephalon / Q000166:cytology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D058953:Neural Stem Cells / Q000502:physiology*; D012249:Rhombencephalon / Q000166:cytology; D043244:Ribonuclease III / Q000235:genetics / Q000378:metabolism; D055748:SOXB1 Transcription Factors / Q000235:genetics / Q000378:metabolism*; D012701:Serotonin / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics; D050819:Transcription Factor Brn-3A / Q000378:metabolism; D014157:Transcription Factors / Q000378:metabolism; D014162:Transfection
chemical_list: D050699:E2F3 Transcription Factor; C490840:E2f3 protein, mouse; C080330:En1 protein, mouse; D018398:Homeodomain Proteins; D035683:MicroRNAs; C543719:Mirn200 microRNA, mouse; D009419:Nerve Tissue Proteins; C494189:Pou4f1 protein, mouse; D055748:SOXB1 Transcription Factors; C527783:Sox2 protein, mouse; D050819:Transcription Factor Brn-3A; D014157:Transcription Factors; C485184:enhanced green fluorescent protein; C433629:homeobox protein PITX3; D049452:Green Fluorescent Proteins; D012701:Serotonin; C509781:Dicer1 protein, mouse; D043244:Ribonuclease III; D053487:DEAD-box RNA Helicases; C031086:5-ethynyl-2'-deoxyuridine; D003857:Deoxyuridine