MEKK3 coordinates with FBW7 to regulate WDR62 stability and neurogenesis

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Dan Xu1,2, Minghui Yao1, Yaqing Wang1

  • 1State 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.

Plos Biology
|December 20, 2018
PubMed

Insights

Mitogen-activated protein kinase kinase kinase 3 (MEKK3) and c-Jun N-terminal kinase (JNK1) regulate WD repeat domain 62 (WDR62) protein stability. This coordinated regulation is crucial for neural progenitor cell balance during brain development.

Area of Science:

  • Neuroscience
  • Molecular Biology
  • Genetics

Background:

  • Mutations in WD repeat domain 62 (WDR62) cause primary microcephaly (MCPH).
  • WDR62 down-regulation leads to neural progenitor cell (NPC) loss, impacting brain size.
  • Mechanisms regulating WDR62 and its role in neurogenesis are not fully understood.

Purpose of the Study:

  • To elucidate the regulatory mechanisms of WDR62 in neurogenesis.
  • To investigate the interaction between WDR62, MEKK3, and JNK signaling pathways.
  • To understand how WDR62 controls neural progenitor cell self-renewal and differentiation.

Main Methods:

  • Co-immunoprecipitation to identify protein complexes.
  • Western blotting to assess protein levels and phosphorylation.
  • Genetic manipulation (gene deletion and transgenic expression) in model systems.
  • Analysis of neural progenitor cell differentiation and proliferation.

Main Results:

  • MEKK3 forms a complex with WDR62, promoting JNK signaling in neurogenesis.
  • Deletion of Mekk3, Wdr62, or Jnk1 causes premature NPC differentiation.
  • WDR62 protein levels are positively regulated by MEKK3 and JNK1.
  • T1053 phosphorylation of WDR62 recruits FBW7, leading to proteasomal degradation.
  • JNK1 expression rescues WDR62 deficiency-induced defects.

Conclusions:

  • A coordinated regulatory network involving MEKK3, FBW7, WDR62, and JNK1 fine-tunes JNK signaling.
  • This network ensures balanced NPC self-renewal and differentiation during cortical development.
  • Dysregulation of this network may contribute to microcephaly and other neurodevelopmental disorders.

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