Trim32 suppresses cerebellar development and tumorigenesis by degrading Gli1/sonic hedgehog signaling
Trim32 suppresses cerebellar development and tumorigenesis by degrading Gli1/sonic hedgehog signaling
复制标题
Trim32 通过降解 Gli1/sonic hedgehog 信号传导抑制小脑发育和肿瘤发生
DOI：
10.1038/s41418-019-0415-5
复制
发表时间：
2020
影响因子：
12.4
通讯作者：
Gao Wei-Qiang
中科院分区：
文献类型：
--
作者：
Wang Minglei;Luo Wenqin;Zhang Yu;Yang Rong;Li Xuefeng;Guo Yanjing;Zhang Chenlu;Yang Ru;Gao Wei-Qiang
Sonic hedgehog（SHH）信号通路在小脑发育过程中对维持颗粒神经元祖细胞（GNP）的生理性自我更新至关重要，其失调导致肿瘤发生。然而，SHH信号在小脑发育过程中是如何控制的，目前还知之甚少。在这里，我们表明，Trim32，细胞命运的决定因素，是不对称地分布在有丝分裂GNP的细胞质中，和基因敲除Trim32保持GNP在增殖和未分化的状态。此外，Trim32基因敲除增强了Ptch 1突变小鼠髓母细胞瘤（MB）形成的发生率。在机制上，Trim32通过其NHL结构域与SHH信号传导的效应子Gli1结合，并通过其RING结构域降解后者以拮抗SHH通路。这些发现提供了一种新的机制，Trim32可能是一个重要的细胞命运调节剂，通过拮抗SHH信号，以促进GNP分化和MB形成的肿瘤抑制剂。
Sonic hedgehog (SHH) signaling is crucial for the maintenance of the physiological self-renewal of granule neuron progenitor cells (GNPs) during cerebellar development, and its dysregulation leads to oncogenesis. However, how SHH signaling is controlled during cerebellar development is poorly understood. Here, we show that Trim32, a cell fate determinant, is distributed asymmetrically in the cytoplasm of mitotic GNPs, and that genetic knockout of Trim32 keeps GNPs at a proliferating and undifferentiated state. In addition, Trim32 knockout enhances the incidence of medulloblastoma (MB) formation in the Ptch1 mutant mice. Mechanistically, Trim32 binds to Gli1, an effector of SHH signaling, via its NHL domain and degrades the latter through its RING domain to antagonize the SHH pathway. These findings provide a novel mechanism that Trim32 may be a vital cell fate regulator by antagonizing the SHH signaling to promote GNPs differentiation and a tumor suppressor in MB formation.