title: TOX3 regulates neural progenitor identity.
abstract: The human genomic locus for the transcription factor TOX3 has been implicated in susceptibility to restless legs syndrome and breast cancer in genome-wide association studies, but the physiological role of TOX3 remains largely unknown. We found Tox3 to be predominantly expressed in the developing mouse brain with a peak at embryonic day E14 where it co-localizes with the neural stem and progenitor markers Nestin and Sox2 in radial glia of the ventricular zone and intermediate progenitors of the subventricular zone. Tox3 is also expressed in neural progenitor cells obtained from the ganglionic eminence of E15 mice that express Nestin, and it specifically binds the Nestin promoter in chromatin immunoprecipitation assays. In line with this, over-expression of Tox3 increased Nestin promoter activity, which was cooperatively enhanced by treatment with the stem cell self-renewal promoting Notch ligand Jagged and repressed by pharmacological inhibition of Notch signaling. Knockdown of Tox3 in the subventricular zone of E12.5 mouse embryos by in utero electroporation of Tox3 shRNA revealed a reduced Nestin expression and decreased proliferation at E14 and a reduced migration to the cortical plate in E16 embryos in electroporated cells. Together, these results argue for a role of Tox3 in the development of the nervous system.
authors.affiliation: Institute of Molecular Biology, (IMB), Mainz, Germany.
authors.forename: Sanjeeb Kumar
authors.initials: SK
authors.lastname: Sahu
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn(2)), Johannes Gutenberg University Medical Center Mainz, Department of Neurology, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors.forename: Alina
authors.initials: A
authors.lastname: Fritz
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Hanns-Dieter-Hüsch-Weg 19, D-55128 Mainz, Germany.
authors.forename: Neha
authors.initials: N
authors.lastname: Tiwari
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn(2)), Johannes Gutenberg University Medical Center Mainz, Department of Neurology, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors.forename: Zsuzsa
authors.initials: Z
authors.lastname: Kovacs
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn(2)), Johannes Gutenberg University Medical Center Mainz, Department of Neurology, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors.forename: Alireza
authors.initials: A
authors.lastname: Pouya
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn(2)), Johannes Gutenberg University Medical Center Mainz, Department of Neurology, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Wüllner
authors.affiliation: Institute of Molecular Biology, (IMB), Mainz, Germany.
authors.forename: Pablo
authors.initials: P
authors.lastname: Bora
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn(2)), Johannes Gutenberg University Medical Center Mainz, Department of Neurology, Langenbeckstr. 1, D-55131 Mainz, Germany.
authors.forename: Teresa
authors.initials: T
authors.lastname: Schacht
authors.affiliation: Institute of Microscopic Anatomy and Neurobiology, University Medical Center of the Johannes-Gutenberg University, Mainz, Germany.
authors.forename: Jan
authors.initials: J
authors.lastname: Baumgart
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Hanns-Dieter-Hüsch-Weg 19, D-55128 Mainz, Germany.
authors.forename: Sophie
authors.initials: S
authors.lastname: Peron
authors.affiliation: Institute of Physiological Chemistry, University Medical Center, Hanns-Dieter-Hüsch-Weg 19, D-55128 Mainz, Germany.
authors.forename: Benedikt
authors.initials: B
authors.lastname: Berninger
authors.affiliation: Institute of Molecular Biology, (IMB), Mainz, Germany. Electronic address: v.tiwari@imb-mainz.de.
authors.forename: Vijay K
authors.initials: VK
authors.lastname: Tiwari
authors.affiliation: Focus Program Translational Neuroscience (FTN), Rhine Main Neuroscience Network (rmn(2)), Johannes Gutenberg University Medical Center Mainz, Department of Neurology, Langenbeckstr. 1, D-55131 Mainz, Germany. Electronic address: axel.methner@gmail.com.
authors.forename: Axel
authors.initials: A
authors.lastname: Methner
mesh_terms: D000818:Animals; D051017:Apoptosis Regulatory Proteins; D002478:Cells, Cultured; D004622:Embryo, Mammalian; D005260:Female; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000187:drug effects / Q000502:physiology*; D055495:Neurogenesis / Q000187:drug effects / Q000235:genetics*; D009474:Neurons / Q000187:drug effects / Q000502:physiology; D011247:Pregnancy; D034741:RNA, Small Interfering / Q000494:pharmacology; D011980:Receptors, Progesterone / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D015534:Trans-Activators
chemical_list: D051017:Apoptosis Regulatory Proteins; D034741:RNA, Small Interfering; D011980:Receptors, Progesterone; C000610490:TOX3 protein, mouse; D015534:Trans-Activators
keywords: Neuronal differentiation; Neuronal progenitors; Notch; Proliferation; Transcription