Lai Chen, Feng Linyin
Institute of Neuroscience, Shanghai Institutes for Biological Science, Chinese Academy of Science, 200031 Shanghai, PR China.
Biochem Biophys Res Commun. 2004 Feb 6;314(2):535-42. doi: 10.1016/j.bbrc.2003.12.131.
Increasing evidences suggest that, after neuregulin (NRG) stimulation, ErbB4 undergoes a series of proteolysis, including gamma-secretase cleavage. The released ErbB4 intracellular domain (EICD) is translocated into nucleus and has a transcriptional function. Although NRG-ErbB4 signaling mediates maturation of oligodendrocytes (OLs), the role of EICD and gamma-secretase in this process remains elusive. Here, we showed that NRG-ErbB4 interaction accumulated EICD in the nucleus and promoted the expression of myelin basic protein expression in OLs. Conversely, inhibitor of ErbB4 or gamma-secretase blocked the capacity of NRG. Nuclear accumulation of EICD did not influence maturation of neurons and astrocytes and early development of OLs. We also found that EICD translocation accorded a temporal pattern, consistent with the developmental gradient of hippocampus. Our data suggest that gamma-secretase activation and EICD nuclear translocation are required for OL maturation induced by NRG, and ErbB4 acts as a functional receptor depending on a new signaling cascade.
越来越多的证据表明，在神经调节蛋白（NRG）刺激后，ErbB4会经历一系列蛋白水解过程，包括γ-分泌酶切割。释放出的ErbB4细胞内结构域（EICD）会转移至细胞核并具有转录功能。尽管NRG-ErbB4信号传导介导少突胶质细胞（OLs）的成熟，但EICD和γ-分泌酶在此过程中的作用仍不清楚。在此，我们表明NRG-ErbB4相互作用使EICD在细胞核中积累，并促进OLs中髓鞘碱性蛋白表达。相反，ErbB4或γ-分泌酶抑制剂会阻断NRG的作用。EICD的核积累不影响神经元和星形胶质细胞的成熟以及OLs的早期发育。我们还发现EICD的转移符合一种时间模式，与海马体的发育梯度一致。我们的数据表明，γ-分泌酶激活和EICD核转位是NRG诱导OL成熟所必需的，并且ErbB4作为一种功能性受体依赖于一种新的信号级联反应。
