Open AccessGSK-3 modulates SHH-driven proliferation in postnatal cerebellar neurogenesis and medulloblastoma
Author(s) -
Jennifer K. Ocasio,
Rolf Dale P. Bates,
Carolyn D. Rapp,
Timothy R. Gershon
Publication year - 2019
Publication title -
development
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.754
H-Index - 325
eISSN - 1477-9129
pISSN - 0950-1991
DOI - 10.1242/dev.177550
Subject(s) - medulloblastoma , sonic hedgehog , biology , wnt signaling pathway , neurogenesis , vismodegib , cancer research , cell growth , microbiology and biotechnology , noggin , cerebellum , medicine , endocrinology , hedgehog signaling pathway , signal transduction , bone morphogenetic protein , genetics , gene
Cerebellar development requires regulated proliferation of cerebellar granule neuron progenitors (CGNPs). Inadequate CGNP proliferation causes cerebellar hypoplasia while excessive CGNP proliferation can cause medulloblastoma, the most common malignant pediatric brain tumor. Although Sonic Hedgehog (SHH) signaling is known to activate CGNP proliferation, the mechanisms down-regulating proliferation are less defined. We investigated CGNP regulation by GSK-3, which down-regulates proliferation in the forebrain, gut and breast by suppressing mitogenic WNT signaling. In striking contrast, we found that co-deleting Gsk-3α and Gsk-3β blocked CGNP proliferation, causing severe cerebellar hypoplasia. The GSK-3 inhibitor CHIR-98014 similarly down-regulated SHH-driven proliferation. Transcriptomic analysis showed activated WNT signaling and up-regulated Cdkn1a in Gsk-3-deleted CGNPs. Ctnnb co-deletion increased CGNP proliferation and rescued cerebellar hypo-proliferation in Gsk-3α/β mutants, demonstrating physiologic control of CGNPs by GSK-3, mediated through WNT. SHH-driven medulloblastomas similarly required GSK-3, as co-deleting Gsk-3α/β blocked tumor growth in medulloblastoma-prone SmoM2 mice. These data show that a GSK-3/WNT axis modulates the developmental proliferation of CGNPs and the pathologic growth of SHH-driven medulloblastoma. The requirement for GSK-3 in SHH-driven proliferation suggests that GSK-3 may be targeted for SHH-driven medulloblastoma therapy.