WNT signaling increases proliferation and impairs differentiation of stem cells in the developing cerebellum

Yanxin Pei, Sonja N. Brun, Shirley L. Markant, William Lento, Paul Gibson, Makoto Mark Taketo, Marco Giovannini, Richard J. Gilbertson, Robert J. Wechsler-Reya

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    69 Scopus citations

    Abstract

    The WNT pathway plays multiple roles in neural development and is crucial for establishment of the embryonic cerebellum. In addition, WNT pathway mutations are associated with medulloblastoma, the most common malignant brain tumor in children. However, the cell types within the cerebellum that are responsive to WNT signaling remain unknown. Here we investigate the effects of canonical WNT signaling on two important classes of progenitors in the developing cerebellum: multipotent neural stem cells (NSCs) and granule neuron precursors (GNPs). We show that WNT pathway activation in vitro promotes proliferation of NSCs but not GNPs. Moreover, mice that express activated β-catenin in the cerebellar ventricular zone exhibit increased proliferation of NSCs in that region, whereas expression of the same protein in GNPs impairs proliferation. Although β-cateninexpressing NSCs proliferate they do not undergo prolonged expansion or neoplastic growth; rather, WNT signaling markedly interferes with their capacity for self-renewal and differentiation. At a molecular level, mutant NSCs exhibit increased expression of c-Myc, which might account for their transient proliferation, but also express high levels of bone morphogenetic proteins and the cyclin-dependent kinase inhibitor p21, which might contribute to their altered self-renewal and differentiation. These studies suggest that the WNT pathway is a potent regulator of cerebellar stem cell growth and differentiation.

    Original languageEnglish (US)
    Pages (from-to)1724-1733
    Number of pages10
    JournalDevelopment
    Volume139
    Issue number10
    DOIs
    StatePublished - May 15 2012

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    Keywords

    • Cerebellum
    • Mouse
    • Self-renewal
    • Stem cell
    • Wnt
    • β-catenin

    ASJC Scopus subject areas

    • Molecular Biology
    • Developmental Biology

    Cite this

    Pei, Y., Brun, S. N., Markant, S. L., Lento, W., Gibson, P., Taketo, M. M., Giovannini, M., Gilbertson, R. J., & Wechsler-Reya, R. J. (2012). WNT signaling increases proliferation and impairs differentiation of stem cells in the developing cerebellum. Development, 139(10), 1724-1733. https://doi.org/10.1242/dev.050104