Regulation of Primary Cilia Disassembly Through HUWE1-Mediated TTBK2 Degradation Plays a Crucial Role in Cerebellar Development and Medulloblastoma Growth

The development of the cerebellum requires the precise regulation of granule neuron progenitor (GNP) proliferation. Although the necessity of primary cilia in supporting GNP proliferation is known, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. In this study, we elucidate the pivotal roles of the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and E3 ubiquitin ligase HUWE1 in GNP proliferation. We found that TTBK2 is highly expressed in proliferating GNPs under Sonic Hedgehog (SHH) signaling, coinciding with active GNP proliferation and the presence of primary cilia. TTBK2 stabilizes primary cilia by inhibiting its disassembly, thereby promoting GNP proliferation in response to SHH. Mechanistically, we identify HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. The disassembly of primary cilia serves as a trigger for GNP differentiation, allowing their migration from the external granule layer (EGL) of the cerebellum to the internal granule layer (IGL) for subsequent maturation. Moreover, we established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. Depletion of TTBK2 exerts inhibitory effects on SHH-MB proliferation, suggesting TTBK2 is a potential therapeutic target for this cancer. In summary, our findings elucidate the mechanism governing cerebellar development and propose a potential anti-cancer strategy for SHH-MB.