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

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

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Title: Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis
Author(s):
Shimada, Issei S.;
Hwang, Sun-Hee;
Somatilaka, Bandarigoda N.;
Wang, Xin;
Skowron, Patryk;
Kim, Jiwoong;
Kim, Min;
Shelton, John M.;
Rajaram, Veena;
Xuan, Zhenyu;
Taylor, Michael D.;
Mukhopadhyay, Saikat
Date Created: 2018-01-30
Item Type: article
Keywords: Show Keywords
Description: Includes supplementary material
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.
Publisher: Cell Press
ISSN: 2211-1247
Source: Cell Reports
Link to Related Resource: http://dx.doi.org/10.1016/j.celrep.2018.01.018
Persistent Link: http://hdl.handle.net/10735.1/6281
Bibliographic Citation: Shimada, Issei S., Sun-Hee Hwang, Bandarigoda N. Somatilaka, Xin Wang, et al. 2018. "Basal suppression of the sonic hedgehog pathway by the G-protein-coupled receptor Gpr161 restricts medulloblastoma pathogenesis." Cell Reports 22(5), 1169-1184, doi:10.1016/j.celrep.2018.01.018
Terms of Use: CC BY-NC-ND 4.0 (Attribution-NonCommercial-NoDerivatives)
©2016
Sponsors: "This work was supported by a recruitment grant from the Cancer Prevention and Research Institute of Texas (R1220), an A-grant from the Alex’s Lemonade Foundation, and an R01 grant from the NIH (1R01GM113023-01)."

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CC BY-NC-ND 4.0 (Attribution-NonCommercial-NoDerivatives) Except where otherwise noted, this item's license is described as CC BY-NC-ND 4.0 (Attribution-NonCommercial-NoDerivatives)