Disruption of protein geranylgeranylation in the cerebellum causes cerebellar hypoplasia and ataxia via blocking granule cell progenitor proliferation

Qi Cheng; Jing Wu; Yingqian Xia; Qing Cheng; Yinjuan Zhao; Peixiang Zhu; Wangling Zhang; Shihu Zhang; Lei Zhang; Yushan Yuan; Chaojun Li; Guiquan Chen; Bin Xue

doi:10.1186/s13041-023-01010-4

Disruption of protein geranylgeranylation in the cerebellum causes cerebellar hypoplasia and ataxia via blocking granule cell progenitor proliferation

Mol Brain. 2023 Feb 13;16(1):24. doi: 10.1186/s13041-023-01010-4.

Authors

Qi Cheng^#¹, Jing Wu^#², Yingqian Xia¹, Qing Cheng³, Yinjuan Zhao⁴, Peixiang Zhu¹, Wangling Zhang¹, Shihu Zhang⁵, Lei Zhang⁶, Yushan Yuan⁶, Chaojun Li⁷, Guiquan Chen^{8

9}, Bin Xue^{10

11}

Affiliations

¹ Medical School of Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China.
² Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China.
³ Department of Obstetrics, Obstetrics and Gynecology Hospital Affiliated to Nanjing Medical University, Nanjing, 210004, Jiangsu, China.
⁴ Collaborative Innovation Center of Sustainable Forestry in Southern China, College of Forestry, Nanjing Forestry University, Nanjing, 210037, Jiangsu, China.
⁵ Department of General Surgery, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing, 210029, China.
⁶ Medical Imaging Center of Fuyang People's Hospital, Fuyang, Anhui Province, China.
⁷ State Key Laboratory of Reproductive Medicine and China International Joint Research Center On Environment and Human Health, Center for Global Health, School of Public Health, Nanjing Medical University, Nanjing, 211166, China. lichaojun@njmu.edu.cn.
⁸ Medical School of Nanjing University, Jiangsu Key Laboratory of Molecular Medicine, Nanjing University, Nanjing, 210093, China. chenguiquan@nju.edu.cn.
⁹ Co-Innovation Center of Neuroregeneration, Nantong University, Nantong, 226001, China. chenguiquan@nju.edu.cn.
¹⁰ Core Laboratory, Sir Run Run Hospital, Nanjing Medical University, Nanjing, 211166, China. xuebin@njmu.edu.cn.
¹¹ Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, 211166, China. xuebin@njmu.edu.cn.

^# Contributed equally.

Abstract

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.

Keywords: Ataxia; Cerebellum; Ggpps; Proliferation; Protein prenylation.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Animals
Ataxia
Cell Proliferation
Cerebellum
Mice
Mice, Knockout
Neural Stem Cells*
Protein Prenylation*

Supplementary concepts

Cerebellar Hypoplasia