Opposite regulation of Wnt/β-catenin and Shh signaling pathways by Rack1 controls mammalian cerebellar development
Opposite regulation of Wnt/β-catenin and Shh signaling pathways by Rack1 controls mammalian cerebellar development
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Rack1 对 Wnt/β-catenin 和 Shh 信号通路的相反调节控制哺乳动物小脑发育
DOI：
10.1073/pnas.1813244116
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发表时间：
2019-03-05
影响因子：
11.1
通讯作者：
Wu, Haitao
中科院分区：
文献类型：
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作者：
Yang, Haihong;Zhu, Qian;Wu, Haitao
小脑的发育依赖于神经干细胞(NSCs)和前体细胞复杂的神经发生、迁移和分化过程。小脑发育缺陷往往会导致运动功能障碍和精神障碍。了解小脑复杂发育的分子机制将有助于开发新的治疗方案。在这里，我们报道了激活的C激酶受体(Rack1)，一种多方面的信号适配器蛋白，以一种细胞类型特异性的方式调节哺乳动物的小脑发育。在小鼠神经干细胞或颗粒神经前体细胞(GNPs)中选择性缺失Rack1，而不是Bergmann神经胶质细胞(BGS)，会导致小脑形态发生的严重缺陷，包括叶和裂隙形成受损。缺乏Rack1的NSCs和GNPs表现出Wnt/β-catenin信号增强，但Sonic hedgehog(Shh)信号减弱。同时删除神经干细胞中的β-连环蛋白，而不是GNPs，可以显著挽救Rack1突变表型。有趣的是，Rack1通过调节组蛋白脱乙酰基酶1(HDAC1)/HDAC2的泛素化和稳定性来控制Shh信号的激活。在发育中的小脑中抑制HDAC1/HDAC2活性会导致Rack1突变体。综上所述，这些结果揭示了Rack1通过对Wnt/β-catenin和Shh信号通路的相反调节来控制哺乳动物小脑发育的先前未知的作用。
The development of the cerebellum depends on intricate processes of neurogenesis, migration, and differentiation of neural stem cells (NSCs) and progenitor cells. Defective cerebellar development often results in motor dysfunctions and psychiatric disorders. Understanding the molecular mechanisms that underlie the complex development of the cerebellum will facilitate the development of novel treatment options. Here, we report that the receptor for activated C kinase (Rack1), a multifaceted signaling adaptor protein, regulates mammalian cerebellar development in a cell type-specific manner. Selective deletion of Rack1 in mouse NSCs or granule neuron progenitors (GNPs), but not Bergmann glial cells (BGs), causes severe defects in cerebellar morphogenesis, including impaired folia and fissure formation. NSCs and GNPs lacking Rack1 exhibit enhanced Wnt/beta-catenin signaling but reduced Sonic hedgehog (Shh) signaling. Simultaneous deletion of beta-catenin in NSCs, but not GNPs, significantly rescues the Rack1 mutant phenotype. Interestingly, Rack1 controls the activation of Shh signaling by regulating the ubiquitylation and stability of histone deacetylase 1 (HDAC1)/HDAC2. Suppression of HDAC1/HDAC2 activity in the developing cerebellum phenocopies the Rack1 mutant. Together, these results reveal a previously unknown role of Rack1 in controlling mammalian cerebellar development by opposite regulation of Wnt/beta-catenin and Shh signaling pathways.