title: Manipulating Wnt signaling at different subcellular levels affects the fate of neonatal neural stem/progenitor cells.
abstract: The canonical Wnt signaling pathway plays an important role in embryogenesis, and the establishment of neurogenic niches. It is involved in proliferation and differentiation of neural progenitors, since elevated Wnt/β-catenin signaling promotes differentiation of neural stem/progenitor cells (NS/PCs1) towards neuroblasts. Nevertheless, it remains elusive how the differentiation program of neural progenitors is influenced by the Wnt signaling output. Using transgenic mouse models, we found that in vitro activation of Wnt signaling resulted in higher expression of β-catenin protein and Wnt/β-catenin target genes, while Wnt signaling inhibition resulted in the reverse effect. Within differentiated cells, we identified three electrophysiologically and immunocytochemically distinct cell types, whose incidence was markedly affected by the Wnt signaling output. Activation of the pathway suppressed gliogenesis, and promoted differentiation of NS/PCs towards a neuronal phenotype, while its inhibition led to suppressed neurogenesis and increased counts of cells of glial phenotype. Moreover, Wnt signaling hyperactivation resulted in an increased incidence of cells expressing outwardly rectifying K+currents, together with inwardly rectifying Na+currents, a typical current pattern of immature neurons, while blocking the pathway led to the opposite effect. Taken together, our data indicate that the Wnt signaling pathway orchestrates neonatal NS/PCs differentiation towards cells with neuronal characteristics, which might be important for nervous tissue regeneration during central nervous system disorders. Furthermore, the transgenic mouse strains used in this study may serve as a convenient tool to manipulate β-catenin-dependent signaling in neural progenitors in the neonatal brain.
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic; 2(nd) Faculty of Medicine, Charles University in Prague, V Uvalu 84, 150 06 Prague 5, Czech Republic. Electronic address: kriska@biomed.cas.cz.
authors.forename: Jan
authors.initials: J
authors.lastname: Kriska
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: honsa@biomed.cas.cz.
authors.forename: Pavel
authors.initials: P
authors.lastname: Honsa
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: david.dzamba@gmail.com.
authors.forename: David
authors.initials: D
authors.lastname: Dzamba
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: obutenko@unito.it.
authors.forename: Olena
authors.initials: O
authors.lastname: Butenko
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: denisa.kolenicova@biomed.cas.cz.
authors.forename: Denisa
authors.initials: D
authors.lastname: Kolenicova
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic; Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: lucie.janeckova@img.cas.cz.
authors.forename: Lucie
authors.initials: L
authors.lastname: Janeckova
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: zuzana.nahacka@img.cas.cz.
authors.forename: Zuzana
authors.initials: Z
authors.lastname: Nahacka
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: ladislav.andera@img.cas.cz.
authors.forename: Ladislav
authors.initials: L
authors.lastname: Andera
authors.affiliation: Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: zbynek.kozmik@img.cas.cz.
authors.forename: Zbynek
authors.initials: Z
authors.lastname: Kozmik
authors.affiliation: Department of Pharmacology, Graduate School of Medicine, Kyoto University, Yoshida Konoé-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: taketo@mfour.med.kyoto-u.ac.jp.
authors.forename: M Mark
authors.initials: MM
authors.lastname: Taketo
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic; Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic. Electronic address: vladimir.korinek@img.cas.cz.
authors.forename: Vladimir
authors.initials: V
authors.lastname: Korinek
authors.affiliation: Institute of Experimental Medicine, Academy of Sciences of the Czech Republic, Videnska 1083, 142 20 Prague 4, Czech Republic; 2(nd) Faculty of Medicine, Charles University in Prague, V Uvalu 84, 150 06 Prague 5, Czech Republic. Electronic address: anderova@biomed.cas.cz.
authors.forename: Miroslava
authors.initials: M
authors.lastname: Anderova
mesh_terms: D000818:Animals; D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / Q000235:genetics / Q000378:metabolism; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002478:Cells, Cultured; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism; D008564:Membrane Potentials / Q000502:physiology; D008822:Mice, Transgenic; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis / Q000502:physiology*; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism*; D009474:Neurons / Q000166:cytology / Q000378:metabolism*; D018408:Patch-Clamp Techniques; D000073940:Transcription Factor 4; D060449:Wnt Signaling Pathway / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051778:Basic Helix-Loop-Helix Leucine Zipper Transcription Factors; C495267:CTNNB1 protein, mouse; C501127:Dkk1 protein, mouse; D036341:Intercellular Signaling Peptides and Proteins; C090743:Tcf4 protein, mouse; D000073940:Transcription Factor 4; D051176:beta Catenin
keywords: Gliogenesis; Ion channel; Neonatal mouse; Neurogenesis; Patch-clamp technique; β-catenin signaling