title: The TLX-miR-219 cascade regulates neural stem cell proliferation in neurodevelopment and schizophrenia iPSC model.
abstract: Dysregulated expression of miR-219, a brain-specific microRNA, has been observed in neurodevelopmental disorders, such as schizophrenia (SCZ). However, its role in normal mammalian neural stem cells (NSCs) and in SCZ pathogenesis remains unknown. We show here that the nuclear receptor TLX, an essential regulator of NSC proliferation and self-renewal, inhibits miR-219 processing. miR-219 suppresses mouse NSC proliferation downstream of TLX. Moreover, we demonstrate upregulation of miR-219 and downregulation of TLX expression in NSCs derived from SCZ patient iPSCs and DISC1-mutant isogenic iPSCs. SCZ NSCs exhibit reduced cell proliferation. Overexpression of TLX or inhibition of miR-219 action rescues the proliferative defect in SCZ NSCs. Therefore, this study uncovers an important role for TLX and miR-219 in both normal neurodevelopment and in SCZ patient iPSC-derived NSCs. Moreover, this study reveals an unexpected role for TLX in regulating microRNA processing, independent of its well-characterized role in transcriptional regulation.
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Kiyohito
authors.initials: K
authors.lastname: Murai
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Sun
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Peng
authors.initials: P
authors.lastname: Ye
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: E
authors.initials: E
authors.lastname: Tian
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.|Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Su
authors.initials: S
authors.lastname: Yang
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.|Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cui
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Guihua
authors.initials: G
authors.lastname: Sun
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Daniel
authors.initials: D
authors.lastname: Trinh
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Olivia
authors.initials: O
authors.lastname: Sun
authors.affiliation: Department of Molecular Immunology, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Teresa
authors.initials: T
authors.lastname: Hong
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Zhexing
authors.initials: Z
authors.lastname: Wen
authors.affiliation: Department of Molecular Immunology, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Markus
authors.initials: M
authors.lastname: Kalkum
authors.affiliation: Department of Diabetes and Metabolic Diseases Research, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Arthur D
authors.initials: AD
authors.lastname: Riggs
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Hongjun
authors.initials: H
authors.lastname: Song
authors.affiliation: Institute for Cell Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|The Solomon Snyder Department of Neuroscience, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.|Department of Psychiatry and Behavioral Science, Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA.
authors.forename: Guo-li
authors.initials: GL
authors.lastname: Ming
authors.affiliation: Division of Stem Cell Biology Research, Department of Developmental and Stem Cell Biology, Cancer Center, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.|Irell and Manella Graduate School of Biological Sciences, Beckman Research Institute of City of Hope, 1500 E. Duarte Road, Duarte, California 91010, USA.
authors.forename: Yanhong
authors.initials: Y
authors.lastname: Shi
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D049109:Cell Proliferation / Q000235:genetics*; D018274:Electroporation; D005786:Gene Expression Regulation / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D047468:Immunoprecipitation; D057026:Induced Pluripotent Stem Cells / Q000378:metabolism*; D013058:Mass Spectrometry; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics; D058953:Neural Stem Cells / Q000378:metabolism*; D055495:Neurogenesis; D057093:Orphan Nuclear Receptors; D012323:RNA Processing, Post-Transcriptional / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D018160:Receptors, Cytoplasmic and Nuclear / Q000235:genetics*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012559:Schizophrenia / Q000235:genetics* / Q000378:metabolism
chemical_list: C412476:DISC1 protein, human; C578248:MIRN219 microRNA, human; C000609357:MIRN219 microRNA, mouse; D035683:MicroRNAs; C088601:NR2E1 protein, human; D009419:Nerve Tissue Proteins; C490258:Nr2e1 protein, mouse; D057093:Orphan Nuclear Receptors; D018160:Receptors, Cytoplasmic and Nuclear; D020796:Receptor, Platelet-Derived Growth Factor alpha