title: WNT3 inhibits cerebellar granule neuron progenitor proliferation and medulloblastoma formation via MAPK activation.
abstract: During normal cerebellar development, the remarkable expansion of granule cell progenitors (GCPs) generates a population of granule neurons that outnumbers the total neuronal population of the cerebral cortex, and provides a model for identifying signaling pathways that may be defective in medulloblastoma. While many studies focus on identifying pathways that promote growth of GCPs, a critical unanswered question concerns the identification of signaling pathways that block mitogenic stimulation and induce early steps in differentiation. Here we identify WNT3 as a novel suppressor of GCP proliferation during cerebellar development and an inhibitor of medulloblastoma growth in mice. WNT3, produced in early postnatal cerebellum, inhibits GCP proliferation by down-regulating pro-proliferative target genes of the mitogen Sonic Hedgehog (SHH) and the bHLH transcription factor Atoh1. WNT3 suppresses GCP growth through a non-canonical Wnt signaling pathway, activating prototypic mitogen-activated protein kinases (MAPKs), the Ras-dependent extracellular-signal-regulated kinases 1/2 (ERK1/2) and ERK5, instead of the classical β-catenin pathway. Inhibition of MAPK activity using a MAPK kinase (MEK) inhibitor reversed the inhibitory effect of WNT3 on GCP proliferation. Importantly, WNT3 inhibits proliferation of medulloblastoma tumor growth in mouse models by a similar mechanism. Thus, the present study suggests a novel role for WNT3 as a regulator of neurogenesis and repressor of neural tumors.
authors.affiliation: Laboratory of Developmental Neurobiology, The Rockefeller University, New York, New York, United States of America.
authors.forename: Sandrine L
authors.initials: SL
authors.lastname: Anne
authors.forename: Eve-Ellen
authors.initials: EE
authors.lastname: Govek
authors.forename: Olivier
authors.initials: O
authors.lastname: Ayrault
authors.forename: Jee Hae
authors.initials: JH
authors.lastname: Kim
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Zhu
authors.forename: David A
authors.initials: DA
authors.lastname: Murphy
authors.forename: Linda
authors.initials: L
authors.lastname: Van Aelst
authors.forename: Martine F
authors.initials: MF
authors.lastname: Roussel
authors.forename: Mary E
authors.initials: ME
authors.lastname: Hatten
mesh_terms: D000818:Animals; D019485:Bone Morphogenetic Proteins / Q000378:metabolism; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000378:metabolism*; D002528:Cerebellar Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D004195:Disease Models, Animal; D004789:Enzyme Activation; D015870:Gene Expression; D020935:MAP Kinase Signaling System; D008527:Medulloblastoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D051379:Mice; D018345:Mice, Knockout; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D058953:Neural Stem Cells / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction; D014161:Transduction, Genetic; D019076:Transgenes; D060508:Wnt3 Protein / Q000235:genetics / Q000378:metabolism*
chemical_list: D019485:Bone Morphogenetic Proteins; D060508:Wnt3 Protein; D020928:Mitogen-Activated Protein Kinases