title: Wnt signaling has opposing roles in the developing and the adult brain that are modulated by Hipk1.
abstract: The canonical Wnt/Wingless pathway is implicated in regulating cell proliferation and cell differentiation of neural stem/progenitor cells. Depending on the context, β-Catenin, a key mediator of the Wnt signaling pathway, may regulate either cell proliferation or differentiation. Here, we show that β-Catenin signaling regulates the differentiation of neural stem/progenitor cells in the presence of the β-Catenin interactor Homeodomain interacting protein kinase-1 gene (Hipk1). On one hand, Hipk1 is expressed at low levels during the entire embryonic forebrain development, allowing β-Catenin to foster proliferation and to inhibit differentiation of neural stem/progenitor cells. On the other hand, Hipk1 expression dramatically increases in neural stem/progenitor cells, residing within the subventricular zone (SVZ), at the time when the canonical Wnt signaling induces cell differentiation. Analysis of mouse brains electroporated with Hipk1, and the active form of β-Catenin reveals that coexpression of both genes induces proliferating neural stem/progenitor cells to escape the cell cycle. Moreover, in SVZ derive neurospheres cultures, the overexpression of both genes increases the expression of the cell-cycle inhibitor P16Ink4. Therefore, our data confirm that the β-Catenin signaling plays a dual role in controlling cell proliferation/differentiation in the brain and indicate that Hipk1 is the crucial interactor able to revert the outcome of β-Catenin signaling in neural stem/progenitor cells of adult germinal niches.
authors.affiliation: Neuroimmunology Unit, Institute of Experimental Neurology, Division of Neuroscience San Raffaele Scientific Institute, 20132 Milan, Italy.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Marinaro
authors.forename: Maria
authors.initials: M
authors.lastname: Pannese
authors.forename: Franziska
authors.initials: F
authors.lastname: Weinandy
authors.forename: Alessandro
authors.initials: A
authors.lastname: Sessa
authors.forename: Andrea
authors.initials: A
authors.lastname: Bergamaschi
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Vania
authors.initials: V
authors.lastname: Broccoli
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Comi
authors.forename: Magdalena
authors.initials: M
authors.lastname: Götz
authors.forename: Gianvito
authors.initials: G
authors.lastname: Martino
authors.forename: Luca
authors.initials: L
authors.lastname: Muzio
mesh_terms: D000375:Aging / Q000378:metabolism*; D000818:Animals; D001921:Brain / Q000254:growth & development* / Q000378:metabolism*; D018398:Homeodomain Proteins / Q000378:metabolism*; D051379:Mice; D008822:Mice, Transgenic; D014018:Tissue Distribution; D051153:Wnt Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway / Q000502:physiology*
chemical_list: D018398:Homeodomain Proteins; D051153:Wnt Proteins