Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis

Issei S. Shimada, Sun Hee Hwang, Bandarigoda N. Somatilaka, Xin Wang, Patryk Skowron, Jiwoong Kim, Min Kim, John M. Shelton, Veena Rajaram, Zhenyu Xuan, Michael D. Taylor, Saikat Mukhopadhyay

Research output: Contribution to journalArticle

15 Scopus citations

Abstract

Sonic hedgehog (Shh) determines cerebellar granule cell (GC) progenitor proliferation and medulloblastoma pathogenesis. However, the pathways regulating GC progenitors during embryogenesis before Shh production by Purkinje neurons and their roles in tumorigenesis remain unclear. The cilium-localized G-protein-coupled receptor Gpr161 suppresses Shh-mediated signaling in the neural tube. Here, by deleting Gpr161 in mouse neural stem cells or GC progenitors, we establish Gpr161 as a tumor suppressor in Shh subtype medulloblastoma. Irrespective of Shh production in the cerebellum, Gpr161 deletion increased downstream activity of the Shh pathway by restricting Gli3-mediated repression, causing more extensive generation and proliferation of GC progenitors. Moreover, earlier deletion of Gpr161 during embryogenesis increased tumor incidence and severity. GC progenitor overproduction during embryogenesis from Gpr161 deletion was cilium dependent, unlike normal development. Low GPR161 expression correlated with poor survival of SHH subtype medulloblastoma patients. Gpr161 restricts GC progenitor production by preventing premature and Shh-dependent pathway activity, highlighting the importance of basal pathway suppression in tumorigenesis. Shimada et al. identify the ciliary G-protein-coupled receptor Gpr161 as a tumor suppressor in Shh subtype medulloblastoma. The authors suggest that Gpr161 restricts premature Shh pathway activity during granule cell progenitor development, implying that cilium-mediated pathway suppression preceding Shh signaling prevents tumorigenesis.

Original languageEnglish (US)
Pages (from-to)1169-1184
Number of pages16
JournalCell Reports
Volume22
Issue number5
DOIs
StatePublished - Jan 30 2018

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Keywords

  • cerebellum
  • G-protein-coupled receptor
  • Gpr161
  • granule cell
  • medulloblastoma
  • primary cilia
  • sonic hedgehog
  • tumor suppressor

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

Cite this

Shimada, I. S., Hwang, S. H., Somatilaka, B. N., Wang, X., Skowron, P., Kim, J., Kim, M., Shelton, J. M., Rajaram, V., Xuan, Z., Taylor, M. D., & Mukhopadhyay, S. (2018). Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis. Cell Reports, 22(5), 1169-1184. https://doi.org/10.1016/j.celrep.2018.01.018