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.
Highlights
During normal cerebellar development, the extraordinary amplification of granule cell progenitors (GCPs) generates vast numbers of granule neurons, up to 45 billion in the human cerebellum
To investigate the role of the Wnts in cerebellar development, we assayed the expression of ten Wnt family members, Wnt1, Wnt3, Wnt3a, Wnt4, Wnt5a, Wnt5b, Wnt6, Wnt7a, Wnt8b and Wnt10b, in the mouse cerebellum from postnatal day 5 (P5) to adult by quantitative PCR
As Sonic Hedgehog (SHH) drives the proliferation of GCPs during postnatal cerebellar development [1], we examined whether WNT3 can antagonize the mitogenic effect of SHH by treating purified GCPs with SHH (3 μg/ml) or with both WNT3 and SHH (Figure 2C)
Summary
The extraordinary amplification of granule cell progenitors (GCPs) generates vast numbers of granule neurons, up to 45 billion in the human cerebellum This unique postnatal expansion of neuronal precursors is driven in large part by the mitogen Sonic Hedgehog (SHH) [1], and deregulation of the SHH signaling pathway in GCPs gives rise to a subset of medulloblastoma [2,3,4,5,6,7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22,23,24], which is the most prevalent metastatic brain tumor of childhood [5,8]. Aberrant WNT signaling affects proliferation and has been implicated in medulloblastoma [3,4,5,9,41,42,43,44,45,46,47,48,49,50], this subset of medulloblastomas is thought to arise outside of the cerebellum from progenitors in the dorsal brainstem [45]
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