Gpr161 functions as a tumor suppressor in medulloblastoma by restricting generation and maintenance of cerebellar granule cell progenitors in a primary cilium-dependent manner

Cerebellar granule cell (GC) progenitors proliferate postnatally in a sonic hedgehog (Shh)-dependent manner, while oncogenic Shh signaling promotes medulloblastoma formation. However, processes regulating generation and maintenance of GC progenitors during embryogenesis, when the predominant mitogen Shh is absent, and their contribution to tumorigenesis is not known. The orphan G-protein-coupled receptor, Gpr161 localizes to primary cilia, and basally suppresses Shh signaling by regulating Gli transcriptional repressor versus activator generation. Here, we demonstrate that either neural stem cell (NSC)- or GC progenitor-specific Gpr161 knockout mice develop Shh-subtype medulloblastomas that are molecularly identical to human tumors. Notably, reduced expression of GPR161 also correlated with poor survival of human SHH-subtype medulloblastoma patients. Gpr161 depletion increased Shh signaling and proliferation of GC progenitors in the external granule layer (EGL) postnatally. However, highest incidence of tumorigenesis was observed upon mid-gestational deletion in NSCs. Interestingly, both generation and proliferation of GC progenitors in the upper rhombic lip and formative EGL, respectively, were increased in the embryonic cerebellum, along with upregulation of Shh signaling. Concomitant disruption of cilia demonstrated that Gpr161 limits GC progenitor generation and proliferation in a cilia-dependent manner. Thus, Gpr161 limits generation and proliferation of GC progenitors both during embryogenesis and postnatal development, irrespective of the presence of Shh. In addition, Gpr161 functions as a bona fide tumor suppressor in Shh-MB, and regulates initiation, natural progression, and prognosis of these debilitating tumors.