Deletion of PDK1 in oligodendrocyte lineage cells causes white matter abnormality and myelination defect in the central nervous system

He Wang; Mengjia Liu; Gang Zou; Long Wang; Wenbin Duan; Xue He; Muhuo Ji; Xiaochuan Zou; Yimin Hu; Jianjun Yang; Guiquan Chen

doi:10.1016/j.nbd.2020.105212

Deletion of PDK1 in oligodendrocyte lineage cells causes white matter abnormality and myelination defect in the central nervous system

Neurobiol Dis. 2021 Jan:148:105212. doi: 10.1016/j.nbd.2020.105212. Epub 2020 Dec 1.

Authors

He Wang¹, Mengjia Liu², Gang Zou³, Long Wang², Wenbin Duan⁴, Xue He¹, Muhuo Ji¹, Xiaochuan Zou², Yimin Hu⁵, Jianjun Yang⁶, Guiquan Chen⁷

Affiliations

¹ Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou 450052, China.
² State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province 210061, China.
³ Department of Anesthesiology, The Second Affiliated Hospital, Nanjing Medical University, 121 Jiangjiayuan Avenue, Nanjing, Jiangsu Province 210003, China.
⁴ Department of General Surgery, The Second Clinical Medical College, Shenzhen People's Hospital, Jinan University, Shenzhen 518000, China.
⁵ Department of General Surgery, The Second Clinical Medical College, Shenzhen People's Hospital, Jinan University, Shenzhen 518000, China. Electronic address: guyueym@njmu.edu.cn.
⁶ Department of Anesthesiology, Pain and Perioperative Medicine, The First Affiliated Hospital of Zhengzhou University, No. 1 East Jianshe Road, Zhengzhou 450052, China. Electronic address: yjyangjj@126.com.
⁷ State Key Laboratory of Pharmaceutical Biotechnology, MOE Key Laboratory of Model Animal for Disease Study, Model Animal Research Center, Nanjing University, 12 Xuefu Avenue, Nanjing, Jiangsu Province 210061, China. Electronic address: chenguiquan@nju.edu.cn.

PMID: 33276084
DOI: 10.1016/j.nbd.2020.105212

Abstract

PDK1 (3-Phosphoinositide dependent protein kinase-1) is a member in the PI3K (phosphatidylinositol 3 kinase) pathway and is implicated in neurodevelopmental disease with microcephaly. Although the role of PDK1 in neurogenesis has been broadly studied, it remains unknown how PDK1 may regulate oligogenesis in the central nervous system (CNS). To address this question, we generated oligodendrocyte (OL) lineage cells specific PDK1 conditional knockout (cKO) mice. We find that PDK1 cKOs display abnormal white matter (WM), massive loss of mature OLs and severe defect in myelination in the CNS. In contrast, these mutants exhibit normal neuronal development and unchanged apoptosis in the CNS. We demonstrate that deletion of PDK1 severely impairs OL differentiation. We show that genetic or pharmacological inhibition of PDK1 causes deficit in the mammalian target of rapamycin (mTor) signaling and down-regulation of Sox10. Together, these results highlight a critical role of PDK1 in OL differentiation during postnatal CNS development.

Keywords: Differentiation; Oligodendrocyte precursor cells; Oligodendrocytes; PDK1; White matter disease.

Publication types

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

MeSH terms

Animals
Cell Differentiation / genetics*
Cell Line
Cell Lineage
Down-Regulation
Mice
Mice, Knockout
Myelin Sheath / metabolism*
Oligodendrocyte Precursor Cells / metabolism*
Oligodendroglia / metabolism*
Pyruvate Dehydrogenase Acetyl-Transferring Kinase / antagonists & inhibitors
Pyruvate Dehydrogenase Acetyl-Transferring Kinase / genetics*
SOXE Transcription Factors / genetics*
SOXE Transcription Factors / metabolism
TOR Serine-Threonine Kinases / metabolism
White Matter / metabolism*

Substances

Pdk1 protein, mouse
Pyruvate Dehydrogenase Acetyl-Transferring Kinase
SOXE Transcription Factors
Sox10 protein, mouse
TOR Serine-Threonine Kinases