title: WNT signaling increases proliferation and impairs differentiation of stem cells in the developing cerebellum.
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-catenin-expressing 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.
authors.affiliation: Tumor Development Program, Sanford-Burnham Medical Research Institute, La Jolla, CA 92037, USA.
authors.forename: Yanxin
authors.initials: Y
authors.lastname: Pei
authors.forename: Sonja N
authors.initials: SN
authors.lastname: Brun
authors.forename: Shirley L
authors.initials: SL
authors.lastname: Markant
authors.forename: William
authors.initials: W
authors.lastname: Lento
authors.forename: Paul
authors.initials: P
authors.lastname: Gibson
authors.forename: Makoto M
authors.initials: MM
authors.lastname: Taketo
authors.forename: Marco
authors.initials: M
authors.lastname: Giovannini
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Gilbertson
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Wechsler-Reya
mesh_terms: D000818:Animals; D002454:Cell Differentiation / Q000235:genetics / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D002531:Cerebellum / Q000166:cytology* / Q000196:embryology / Q000378:metabolism*; D005434:Flow Cytometry; D051379:Mice; D058953:Neural Stem Cells / Q000166:cytology* / Q000378:metabolism*; D060888:Real-Time Polymerase Chain Reaction; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D051176:beta Catenin