title: Severe alterations of cerebellar cortical development after constitutive activation of Wnt signaling in granule neuron precursors.
abstract: The Wnt/β-catenin signaling pathway plays crucial roles in early hindbrain formation, and its constitutive activity is associated with a subset of human medulloblastoma, a malignant childhood tumor of the posterior fossa. However, the precise function of Wnt/β-catenin signaling during cerebellar development is still elusive. We generated Math1-cre::Apc(Fl/Fl) mice with a conditional knockout for the Adenomatosis polyposis coli (Apc) gene that displayed a constitutive activity of Wnt/β-catenin signaling in cerebellar granule neuron precursors. Such mice showed normal survival without any tumor formation but had a significantly smaller cerebellum with a complete disruption of its cortical histoarchitecture. The activation of the Wnt/β-catenin signaling pathway resulted in a severely inhibited proliferation and premature differentiation of cerebellar granule neuron precursors in vitro and in vivo. Mutant mice hardly developed an internal granular layer, and layering of Purkinje neurons was disorganized. Clinically, these mice presented with significantly impaired motor coordination and ataxia. In summary, we conclude that cerebellar granule neurons essentially require appropriate levels of Wnt signaling to balance their proliferation and differentiation.
authors.affiliation: Center for Neuropathology, Ludwig Maximilians University, 81377 Munich, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Lorenz
authors.forename: Markus
authors.initials: M
authors.lastname: Deutschmann
authors.forename: Julia
authors.initials: J
authors.lastname: Ahlfeld
authors.forename: Catharina
authors.initials: C
authors.lastname: Prix
authors.forename: Arend
authors.initials: A
authors.lastname: Koch
authors.forename: Ron
authors.initials: R
authors.lastname: Smits
authors.forename: Riccardo
authors.initials: R
authors.lastname: Fodde
authors.forename: Hans A
authors.initials: HA
authors.lastname: Kretzschmar
authors.forename: Ulrich
authors.initials: U
authors.lastname: Schüller
mesh_terms: D025601:Adenomatous Polyposis Coli Protein / Q000235:genetics; D000818:Animals; D001259:Ataxia / Q000209:etiology; D002454:Cell Differentiation; D049109:Cell Proliferation; D002540:Cerebral Cortex / Q000254:growth & development* / Q000473:pathology; D051379:Mice; D018345:Mice, Knockout; D019957:Motor Skills Disorders / Q000209:etiology; D058953:Neural Stem Cells / Q000378:metabolism*; D009474:Neurons / Q000378:metabolism; D015398:Signal Transduction; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D025601:Adenomatous Polyposis Coli Protein; D051153:Wnt Proteins