Basal Suppression of the Sonic Hedgehog Pathway by the G-Protein-Coupled Receptor Gpr161 Restricts Medulloblastoma Pathogenesis
Open accessAbstract
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.
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KIF7 becomes enriched at ciliary tips during Hedgehog pathway activation and acts as both a positive and negative regulator of SHH signalling by modifying ciliary architecture.
“KIF7, also becomes enriched in ciliary tips during activation of HH signalling 136, 137, where it. functions as both a positive and negative regulator of SHH signalling by modifying ciliary architecture 136, 137.”
From Cellular signalling by primary cilia in development, organ function and disease (2019) · cites this paper as [137]
The Introduction discusses cilium-dependent activation and repression of SHH signalling, but does not attribute either role to KIF7. Searches for KIF7, its enrichment at ciliary tips, and its effect on ciliary architecture found no passage addressing those claims; the Discussion instead mentions Kif3a and Gpr161. Page numbers were not available in our copy. (LLM, conf=0.77)
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Regulatory mechanisms governing GLI proteins in hedgehog signaling
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Identification and spatiotemporal expression of gpr161 genes in zebrafish
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Zebrafish GPR161 Contributes to Basal Hedgehog Repression in a Tissue-specific MannerPreprint
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- Authors
- 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.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- Hospital for Sick Children (CA)
- The University of Texas at Dallas (US)
- Corresponding author
- Mukhopadhyay, Saikat
- ORCID
- Venue
- Cell Reports
- Publisher
- Elsevier BV
- Published
- 2018-01
- Volume
- 22
- Issue
- 5
- Pages
- 1169-1184
- ISSN
- 2211-1247 (ISSN-L)
- PMC
- PMC5813698
- OpenAlex
- W2787601395
- Cited by
- 52
- References
- 47
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 6 · 2023: 4 · 2022: 4 · 2021: 9 · 2020: 5 · 2019: 15 · 2018: 4
- FWCI
- 2.93
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Licence
- Locations
- Cell Reports (publishedVersion, cc-by-nc-nd)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Funders
- Cancer Prevention and Research Institute of Texas (R1220)
- National Institutes of Health (1R01GM113023-01)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Hedgehog Signaling Pathway Studies
- Health Sciences › Medicine › Genetics › Glioma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and Kidney Cyst Diseases
- Keywords
- GPR161, Sonic hedgehog signaling, medulloblastoma, tumor suppressor, primary cilia, G protein-coupled receptors, neural stem cells, cerebellar development, Purkinje cells, patient survival
- MeSH terms
- Animals, Cerebellar Neoplasms, Humans, Medulloblastoma, Mice, Inbred C57BL, Mice, Knockout, Receptors, G-Protein-Coupled, Embryonic Development, Mice, Hedgehog Proteins, Neurogenesis, Neural Stem Cells
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