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PDK1 Regulates the Maintenance of Cell Body and the Development of Dendrites of Purkinje Cells by pS6 and PKCγ.

Authors
  • Liu, Rui1
  • Xu, Min1
  • Zhang, Xiao-Yang2
  • Zhou, Min-Jie1
  • Zhou, Bing-Yao1
  • Qi, Cui1
  • Song, Bo2
  • Fan, Qi1
  • You, Wei-Yan1
  • Zhu, Jing-Ning2
  • Yang, Zhong-Zhou3
  • Gao, Jun4, 5
  • 1 Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China. , (China)
  • 2 Key Laboratory of Pharmaceutical Biotechnology, Department of Physiology, and Institute for Brain Sciences, School of Life Sciences, Nanjing University, Nanjing 210023, People's Republic of China. , (China)
  • 3 State Key Laboratory of Pharmaceutical Biotechnology, Department of Cardiology, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School and MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, Nanjing, 210061, People's Republic of China. , (China)
  • 4 Department of Neurobiology, Key Laboratory of Human Functional Genomics of Jiangsu, Nanjing Medical University, Nanjing 211166, Jiangsu, People's Republic of China [email protected] , (China)
  • 5 Department of Rehabilitation Medicine, Jiangsu Shengze Hospital Affiliated with Nanjing Medical University, Suzhou 215228, Jiangsu, People's Republic of China. , (China)
Type
Published Article
Journal
Journal of Neuroscience
Publisher
Society for Neuroscience
Publication Date
Jul 15, 2020
Volume
40
Issue
29
Pages
5531–5548
Identifiers
DOI: 10.1523/JNEUROSCI.2496-19.2020
PMID: 32487697
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

3-Phosphoinositide-dependent protein kinase-1 (PDK1) plays a critical role in the development of mammalian brain. Here, we investigated the role of PDK1 in Purkinje cells (PCs) by generating the PDK1-conditional knock-out mice (cKO) through crossing PV-cre or Pcp2-cre mice with Pdk1fl/fl mice. The male mice were used in the behavioral testing, and the other experiments were performed on mice of both sexes. These PDK1-cKO mice displayed decreased cerebellar size and impaired motor balance and coordination. By the electrophysiological recording, we observed the reduced spontaneous firing of PCs from the cerebellar slices of the PDK1-cKO mice. Moreover, the cell body size of PCs in the PDK1-cKO mice was time dependently reduced compared with that in the control mice. And the morphologic complexity of PCs was also decreased after PDK1 deletion. These effects may have contributed to the reduction of the rpS6 (reduced ribosomal protein S6) phosphorylation and the PKCγ expression in PDK1-cKO mice since the upregulation of pS6 by treatment of 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-1, the agonist of mTOR1, partly rescued the reduction in the cell body size of the PCs, and the delivery of recombinant adeno-associated virus-PKCγ through cerebellar injection rescued the reduced complexity of the dendritic arbor in PDK1-cKO mice. Together, our data suggest that PDK1, by regulating rpS6 phosphorylation and PKCγ expression, controls the cell body maintenance and the dendritic development in PCs and is critical for cerebellar motor coordination.SIGNIFICANCE STATEMENT Here, we show the role of 3-phosphoinositide-dependent protein kinase-1 (PDK1) in Purkinje cells (PCs). The ablation of PDK1 in PCs resulted in a reduction of cell body size, and dendritic complexity and abnormal spontaneous firing, which attributes to the motor defects in PDK1-conditional knock-out (cKO) mice. Moreover, the ribosomal protein S6 (rpS6) phosphorylation and the expression of PKCγ are downregulated after the ablation of PDK1. Additionally, upregulation of rpS6 phosphorylation by3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-1 partly rescued the reduction in cell body size of PCs, and the overexpression of PKCγ in PDK1-KO PCs rescued the reduction in the dendritic complexity. These findings indicate that PDK1 contributes to the maintenance of the cell body and the dendritic development of PCs by regulating rpS6 phosphorylation and PKCγ expression. Copyright © 2020 the authors.

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