Abstract
Development of the cerebellum requires precise regulation of granule neuron progenitor (GNP) proliferation. Although it is known that primary cilia are necessary to support GNP proliferation, the exact molecular mechanism governing primary cilia dynamics within GNPs remains elusive. Here, we establish the pivotal roles for the centrosomal kinase TTBK2 (Tau tubulin kinase-2) and the E3 ubiquitin ligase HUWE1 in GNP proliferation. We show 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 their 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. 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 have established a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type. In summary, our findings reveal the mechanism governing cerebellar development and highlight a potential anti-cancer strategy for SHH-MB.
Overview
- The study investigates the role of primary cilia in granule neuron progenitor (GNP) proliferation during cerebellar development. The study tests the hypothesis that precise regulation of GNP proliferation is necessary for cerebellar development. The methodology used includes the use of Sonic Hedgehog (SHH) signaling and the identification of key molecules involved in GNP proliferation, including TTBK2 and HUWE1. The primary objective of the study is to understand the molecular mechanism governing primary cilia dynamics within GNPs and its role in cerebellar development.
Comparative Analysis & Findings
- The study compares the outcomes observed under SHH signaling and identifies TTBK2 as a key molecule involved in GNP proliferation. The study also identifies HUWE1 as a novel centrosomal E3 ligase that facilitates primary cilia disassembly by targeting TTBK2 degradation. The key findings of the study reveal that TTBK2 stabilizes primary cilia by inhibiting their disassembly, thereby promoting GNP proliferation in response to SHH. 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. The study also establishes a link between TTBK2 and SHH-type medulloblastoma (SHH-MB), a tumor characterized by uncontrolled GNP proliferation. TTBK2 depletion inhibits SHH-MB proliferation, indicating that TTBK2 may be a potential therapeutic target for this cancer type.
Implications and Future Directions
- The study's findings have significant implications for the field of research and clinical practice. The study highlights the importance of precise regulation of GNP proliferation in cerebellar development and identifies key molecules involved in this process. The study also establishes a link between TTBK2 and SHH-MB, a tumor characterized by uncontrolled GNP proliferation. The study suggests that TTBK2 may be a potential therapeutic target for SHH-MB. Future research directions could include further investigation of the role of primary cilia in GNP proliferation and the development of targeted therapies for SHH-MB.