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A Multiprotein Complex Involves in Regulation of Cortical Neuronal Migration
In the development process of brain, neuronal progenitor cells (NPCs) undergo proliferation, differentiation, migration and maturation to form the normal six-layer structure of cerebral cortex and functional neuronal connectivity. Defects in neuronal migration during brain development would lead to several neurological diseases, such as primary autosomal recessive microcephaly (MCPH) and lissencephaly. Transforming growth factor-β (TGF-β) signaling pathway has been reported to control several developmental processes, like axon specification, axon outgrowth, and neuronal migration, however, the underlying molecular mechanisms of how TGF-β signaling pathway regulates neuronal migration remains unclear.
The scientists from XU Zhiheng’s group at the Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, found that TGF-β-activated kinase 1 (TAK1) played an important role in TGF-β signaling controlled neuronal migration through regulation of c-Jun N-terminal kinase (JNK) activity..
They employed in utero electroporation to knock down or knock out the expression of TAK1 or JNK2 in NPCs, and found that knockdown or knockout of TAK1 and JNK2 could impair neuronal migration. They also showed that the defects in neuronal migration caused by knockdown of Tβr2 (type II TGF-β receptor) or TAK1 could be rescued by over-expression of TAK1 and JNK2, respectively. Furthermore, they found that TAK1 could interact with small GTP binding protein, RAC1 (ras-related C3 botulinum toxin substrate 1), and two scaffold proteins of JNK pathway, WDR62 (the microcephaly associated protein) and POSH to form a protein complex.
The results proposed a molecular model in which TGF-β activates JNK2 through a novel protein complex consisting of RAC1, TAK1 and Mitogen-activated protein kinase kinase 4/7 (MKK4/7). This complex is organized by WDR62 and POSH and plays an essential role in neuronal migration during brain development.
This work entitled “A Novel c-Jun N-terminal Kinase (JNK) Signaling Complex Involved in Neuronal Migration during Brain Development” was on-line published in Journal of Biological Chemistry (JBC) on May 27th, 2016 (DOI:10.1074/jbc.M116.716811). This paper was selected as the Paper of the Week and as the cover paper of this issue of JBC. In addition, JBC also profiled ZHANG Feng, the first author of the article, to highlight scientist at early stages in their careers.
This work is supported by grants from National Natural Science Foundation of China and the Ministry of Science and Technology of China.
Scheme for a multiprotein complex involved in the TGF-β-JNK signaling pathway and neuronal migration. (Image by IGDB)
Dr. XU Zhiheng