Severe alterations of cerebellar cortical development after constitutive activation of Wnt signaling in granule neuron precursors
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Severe alterations of cerebellar cortical development after constitutive activation of Wnt signaling in granule neuron precursors. / Lorenz, Andreas; Deutschmann, Markus; Ahlfeld, Julia; Prix, Catharina; Koch, Arend; Smits, Ron; Fodde, Riccardo; Kretzschmar, Hans A; Schüller, Ulrich.
In: MOL CELL BIOL, Vol. 31, No. 16, 08.2011, p. 3326-38.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - Severe alterations of cerebellar cortical development after constitutive activation of Wnt signaling in granule neuron precursors
AU - Lorenz, Andreas
AU - Deutschmann, Markus
AU - Ahlfeld, Julia
AU - Prix, Catharina
AU - Koch, Arend
AU - Smits, Ron
AU - Fodde, Riccardo
AU - Kretzschmar, Hans A
AU - Schüller, Ulrich
PY - 2011/8
Y1 - 2011/8
N2 - 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.
AB - 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.
KW - Adenomatous Polyposis Coli Protein
KW - Animals
KW - Ataxia
KW - Cell Differentiation
KW - Cell Proliferation
KW - Cerebral Cortex
KW - Mice
KW - Mice, Knockout
KW - Motor Skills Disorders
KW - Neural Stem Cells
KW - Neurons
KW - Signal Transduction
KW - Wnt Proteins
KW - Journal Article
KW - Research Support, Non-U.S. Gov't
U2 - 10.1128/MCB.05718-11
DO - 10.1128/MCB.05718-11
M3 - SCORING: Journal article
C2 - 21690300
VL - 31
SP - 3326
EP - 3338
JO - MOL CELL BIOL
JF - MOL CELL BIOL
SN - 0270-7306
IS - 16
ER -