MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis

Dan Xu; Minghui Yao; Yaqing Wang; Ling Yuan; Joerg D Hoeck; Jingwen Yu; Liang Liu; Yvonne Y C Yeap; Weiya Zhang; Feng Zhang; Yinghang Feng; Tiantian Ma; Yujie Wang; Dominic C H Ng; Xiaoyin Niu; Bing Su; Axel Behrens; Zhiheng Xu

doi:10.1371/journal.pbio.2006613

MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis

PLoS Biol. 2018 Dec 19;16(12):e2006613. doi: 10.1371/journal.pbio.2006613. eCollection 2018 Dec.

Authors

Dan Xu^{1

2}, Minghui Yao¹, Yaqing Wang¹, Ling Yuan³, Joerg D Hoeck⁴, Jingwen Yu¹, Liang Liu¹, Yvonne Y C Yeap⁵, Weiya Zhang¹, Feng Zhang¹, Yinghang Feng⁶, Tiantian Ma¹, Yujie Wang², Dominic C H Ng⁵, Xiaoyin Niu⁷, Bing Su^{7

8}, Axel Behrens^{9

10}, Zhiheng Xu^{1

6

11}

Affiliations

¹ State Key Laboratory of Molecular Developmental Biology, CAS Center for Excellence in Brain Science and Intelligence Technology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
² College of Biological Science and Engineering, Institute of Life Sciences, Fuzhou University, Fuzhou, China.
³ Center for Medical Genetics, School of Life Sciences, Central South University, Changsha, Hunan, China.
⁴ CR-UK London Research Institute, London, United Kingdom.
⁵ School of Biomedical Science, Faculty of Medicine, University of Queensland, St Lucia, Australia.
⁶ Sino-Danish College, University of Chinese Academy of Science, Beijing, China.
⁷ Shanghai Institute of Immunology, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
⁸ Department of Immunobiology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
⁹ Adult Stem Cell Laboratory, The Francis Crick Institute, London, United Kingdom.
¹⁰ King's College London, Faculty of Life Sciences and Medicine, Guy's Campus, London, United Kingdom.
¹¹ Parkinson's Disease Center, Beijing Institute for Brain Disorders, Beijing, China.

Abstract

Mutations of WD repeat domain 62 (WDR62) lead to autosomal recessive primary microcephaly (MCPH), and down-regulation of WDR62 expression causes the loss of neural progenitor cells (NPCs). However, how WDR62 is regulated and hence controls neurogenesis and brain size remains elusive. Here, we demonstrate that mitogen-activated protein kinase kinase kinase 3 (MEKK3) forms a complex with WDR62 to promote c-Jun N-terminal kinase (JNK) signaling synergistically in the control of neurogenesis. The deletion of Mekk3, Wdr62, or Jnk1 resulted in phenocopied defects, including premature NPC differentiation. We further showed that WDR62 protein is positively regulated by MEKK3 and JNK1 in the developing brain and that the defects of wdr62 deficiency can be rescued by the transgenic expression of JNK1. Meanwhile, WDR62 is also negatively regulated by T1053 phosphorylation, leading to the recruitment of F-box and WD repeat domain-containing protein 7 (FBW7) and proteasomal degradation. Our findings demonstrate that the coordinated reciprocal and bidirectional regulation among MEKK3, FBW7, WDR62, and JNK1, is required for fine-tuned JNK signaling for the control of balanced NPC self-renewal and differentiation during cortical development.

Publication types

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

MeSH terms

Animals
Cell Cycle Proteins / metabolism*
Cell Differentiation
F-Box-WD Repeat-Containing Protein 7 / genetics
F-Box-WD Repeat-Containing Protein 7 / physiology*
Female
HEK293 Cells
Humans
MAP Kinase Kinase Kinase 3 / genetics
MAP Kinase Kinase Kinase 3 / physiology*
MAP Kinase Signaling System
Male
Mice
Mice, Knockout
Mice, Transgenic
Microcephaly / genetics
Microcephaly / physiopathology
Microtubule-Associated Proteins / metabolism*
Mitogen-Activated Protein Kinase 8 / metabolism
Nerve Tissue Proteins / metabolism
Neural Stem Cells / metabolism
Neurogenesis / physiology
Phosphorylation
Protein Binding
Rats
Rats, Sprague-Dawley
Signal Transduction

Substances

Cell Cycle Proteins
F-Box-WD Repeat-Containing Protein 7
Microtubule-Associated Proteins
Nerve Tissue Proteins
WDR62 protein, mouse
Mitogen-Activated Protein Kinase 8
MAP Kinase Kinase Kinase 3

Supplementary concepts

Autosomal Recessive Primary Microcephaly

Grants and funding

National Natural Science Foundation (grant number 31430037/31730108/31471132/31571038). Received by ZX. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation (grant number 31600841). Received by DX. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Strategic Priority Research Program and Innovation Program of the Chinese Academy of Sciences (grant number XDBS1020100, XDA16010306, QYZDJ-SSW-SMC007 and GJHZ1827). Received by ZX. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Shanghai brain-intelligence project from STCSM (grant number 16JC1420500). Received by ZX. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Beijing brain project (grant number Z161100002616004). Received by ZX. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Key research and development program of Hunan province (grant number 2018DK2012). Received by LY. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Shanghai Science and Technology Committee (grant number 16410723300). Received by BS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. National Natural Science Foundation (grant number 31470845, 81430033). Received by BS. The funder had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.