Mutations of WD40-repeat protein 62 (WDR62) have been identified recently to be the second major cause of human MCPH (autosomal recessive primary microcephaly), a neurodevelopmental disorder characterized by decreased brain size and mental retardation. However, the underlying pathomechanism is unclear.
Dr. Zhiheng Xu’s laboratory from the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences investigated the molecular function of WDR62 in brain development and the pathological role of WDR62 mutations. They find that WDR62 knockdown leads to premature differentiation of neural progenitor cells (NPCs) and depletion of NPCs. The defect can be rescued by wild-type human WDR62 but not by the MCPH-associated WDR62 mutants. In addition, they 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 their findings indicate that WDR62 is required for the maintenance of NPC and proper neurogenesis via JNK1, and provide an insight into the molecular mechanisms underlying MCPH pathogenesis.
This work with Dan Xu as the first author has been published in Cell Reports in the form of an article (
DOI:10.1016/j.celrep.2013.12.016). This research was supported by grants from Chinese Academy of Sciences, Ministry of Science and Technology, and National Natural Science Foundation of China.
AUTHOR CONTACT:
Zhiheng Xu, Ph.D.
Institute of Genetics and Developmetnal Biology, Chinese Academy of Sciences, Beijing, China.
From Xu et al. (2014). Cell Reports 6(1):104-16 (Article).
Graphical Abstract: During brain development, knockdown of WDR62 leads to arrest of most cells to the IZ, due to the depletion of NPCs and defects in neuronal migration. WDR62 controls the self-renew of NPCs during corticogenesis through the regulation of JNK activity. This occurs by affecting the localization of activated JNK to orchestrate the proper formation of the spindle and by this means symmetric or asymmetric division of NPCs.
