title: Microcephaly-associated protein WDR62 regulates neurogenesis through JNK1 in the developing neocortex.
abstract: Mutations of WD40-repeat protein 62 (WDR62) have been identified recently to cause human MCPH (autosomal-recessive primary microcephaly), a neurodevelopmental disorder characterized by decreased brain size. However, the underlying mechanism is unclear. Here, we investigate the function of WDR62 in brain development and the pathological role of WDR62 mutations. We find that WDR62 knockdown leads to premature differentiation of neural progenitor cells (NPCs). The defect can be rescued by wild-type human WDR62, but not by the five MCPH-associated WDR62 mutants. We demonstrate that WDR62 acts upstream of JNK signaling in the control of neurogenesis. Depletion of JNK1 and WDR62 incurs very similar defects including abnormal spindle formation and mitotic division of NPCs as well as premature NPC differentiation during cortical development. Thus, our findings indicate that WDR62 is required for proper neurogenesis via JNK1 and provide an insight into the molecular mechanisms underlying MCPH pathogenesis.
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, West Lincui Road, Chaoyang District, Beijing 100101, China.
authors.forename: Dan
authors.initials: D
authors.lastname: Xu
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, West Lincui Road, Chaoyang District, Beijing 100101, China.
authors.forename: Feng
authors.initials: F
authors.lastname: Zhang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, West Lincui Road, Chaoyang District, Beijing 100101, China.
authors.forename: Yaqing
authors.initials: Y
authors.lastname: Wang
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, West Lincui Road, Chaoyang District, Beijing 100101, China.
authors.forename: Yiming
authors.initials: Y
authors.lastname: Sun
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, West Lincui Road, Chaoyang District, Beijing 100101, China; Center of Parkinson's Disease, Beijing Institute for Brain Disorders, Beijing 100101, China. Electronic address: zhxu@genetics.ac.cn.
authors.forename: Zhiheng
authors.initials: Z
authors.lastname: Xu
mesh_terms: D000818:Animals; D018797:Cell Cycle Proteins; D002478:Cells, Cultured; D006801:Humans; D051379:Mice; D008831:Microcephaly / Q000235:genetics*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D009154:Mutation; D019579:Neocortex / Q000166:cytology / Q000196:embryology / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism*; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley
chemical_list: D018797:Cell Cycle Proteins; D009419:Nerve Tissue Proteins; C552527:WDR62 protein, human; D048055:Mitogen-Activated Protein Kinase 8