Medical School of Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China.
Mol Brain. 2023 Feb 13;16(1):24. doi: 10.1186/s13041-023-01010-4.
The prenylation of proteins is involved in a variety of biological functions. However, it remains unknown whether it plays an important role in the morphogenesis of the cerebellum. To address this question, we generated a mouse model, in which the geranylgeranyl pyrophosphate synthase (Ggps1) gene is inactivated in neural progenitor cells in the developing cerebellum. We report that conditional knockout (cKO) of Ggps1 leads to severe ataxia and deficient locomotion. To identify the underlying mechanisms, we completed a series of cellular and molecular experiments. First, our morphological analysis revealed significantly decreased population of granule cell progenitors (GCPs) and impaired proliferation of GCPs in the developing cerebellum of Ggps1 cKO mice. Second, our molecular analysis showed increased expression of p21, an important cell cycle regulator in Ggps1 cKO mice. Together, this study highlights a critical role of Ggpps-dependent protein prenylation in the proliferation of cerebellar GCPs during cerebellar development.
蛋白质的类异戊二烯化参与了多种生物学功能。然而，目前尚不清楚它在小脑形态发生中是否起着重要作用。为了解决这个问题，我们生成了一种小鼠模型，其中神经祖细胞中的香叶基香叶基焦磷酸合酶（Ggps1）基因在发育中的小脑被失活。我们报告说，Ggps1 的条件敲除（cKO）导致严重的共济失调和运动功能缺陷。为了确定潜在的机制，我们完成了一系列细胞和分子实验。首先，我们的形态分析显示，Ggps1 cKO 小鼠发育中的小脑颗粒细胞祖细胞（GCPs）数量明显减少，增殖受损。其次，我们的分子分析显示，Ggps1 cKO 小鼠中一种重要的细胞周期调节剂 p21 的表达增加。总之，这项研究强调了 Ggpps 依赖性蛋白类异戊二烯化在小脑发育过程中小脑 GCP 增殖中的关键作用。
