Wnt signaling has opposing roles in the developing and the adult brain that are modulated by Hipk1

Cinzia Marinaro, Maria Pannese, Franziska Weinandy, Alessandro Sessa, Andrea Bergamaschi, Makoto M. Taketo, Vania Broccoli, Giancarlo Comi, Magdalena Götz, Gianvito Martino, Luca Muzio

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)2415-2427
Number of pages13
JournalCerebral Cortex
Volume22
Issue number10
DOIs
Publication statusPublished - Oct 2012

Keywords

  • β-Catenin
  • Hipk1
  • Stem cells
  • SVZ
  • Wnt

ASJC Scopus subject areas

  • Cognitive Neuroscience
  • Cellular and Molecular Neuroscience

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