Department of Neurobiology, Beijing Institute of Basic Medical Sciences, 100850 Beijing, China.
School of Basic Medical Sciences, College of Medicine, Qingdao University, Qingdao 421001, China.
Proc Natl Acad Sci U S A. 2022 Aug 23;119(34):e2202821119. doi: 10.1073/pnas.2202821119. Epub 2022 Aug 15.
Sonic hedgehog (Shh) signaling plays a critical role in regulating cerebellum development by maintaining the physiological proliferation of granule neuron precursors (GNPs), and its dysregulation leads to the oncogenesis of medulloblastoma. O-GlcNAcylation (O-GlcNAc) of proteins is an emerging regulator of brain function that maintains normal development and neuronal circuitry. Here, we demonstrate that O-GlcNAc transferase (OGT) in GNPs mediate the cerebellum development, and the progression of the Shh subgroup of medulloblastoma. Specifically, OGT regulates the neurogenesis of GNPs by activating the Shh signaling pathway via O-GlcNAcylation at S355 of GLI family zinc finger 2 (Gli2), which in turn promotes its deacetylation and transcriptional activity via dissociation from p300, a histone acetyltransferases. Inhibition of OGT via genetic ablation or chemical inhibition improves survival in a medulloblastoma mouse model. These data uncover a critical role for O-GlcNAc signaling in cerebellar development, and pinpoint a potential therapeutic target for Shh-associated medulloblastoma.
Sonic hedgehog（Shh）信号通路通过维持颗粒神经元前体细胞（GNPs）的生理增殖，在调节小脑发育中发挥着关键作用，其失调会导致成神经管细胞瘤的发生。蛋白质的 O-GlcNAc 修饰（O-GlcNAc）是大脑功能的一种新兴调节剂，可维持正常的发育和神经元回路。在这里，我们证明 GNPs 中的 O-GlcNAc 转移酶（OGT）通过 O-GlcNAc 化Gli 家族锌指蛋白 2（Gli2）的 S355 激活 Shh 信号通路，从而调节 GNPs 的神经发生，Gli2 是 Shh 亚群成神经管细胞瘤的关键转录因子。这反过来又通过与组蛋白乙酰转移酶 p300 分离来促进其去乙酰化和转录活性。通过基因敲除或化学抑制 OGT 可改善成神经管细胞瘤小鼠模型的存活率。这些数据揭示了 O-GlcNAc 信号在小脑发育中的关键作用，并确定了 Shh 相关成神经管细胞瘤的潜在治疗靶点。
