Itoh Motoyuki, Kim Cheol-Hee, Palardy Gregory, Oda Takaya, Jiang Yun-Jin, Maust Donovan, Yeo Sang-Yeob, Lorick Kevin, Wright Gavin J, Ariza-McNaughton Linda, Weissman Allan M, Lewis Julian, Chandrasekharappa Settara C, Chitnis Ajay B
Laboratory of Molecular Genetics, NICHD, NIH, Bethesda, MD 20892, USA.
Dev Cell. 2003 Jan;4(1):67-82. doi: 10.1016/s1534-5807(02)00409-4.
Lateral inhibition, mediated by Notch signaling, leads to the selection of cells that are permitted to become neurons within domains defined by proneural gene expression. Reduced lateral inhibition in zebrafish mib mutant embryos permits too many neural progenitors to differentiate as neurons. Positional cloning of mib revealed that it is a gene in the Notch pathway that encodes a RING ubiquitin ligase. Mib interacts with the intracellular domain of Delta to promote its ubiquitylation and internalization. Cell transplantation studies suggest that mib function is essential in the signaling cell for efficient activation of Notch in neighboring cells. These observations support a model for Notch activation where the Delta-Notch interaction is followed by endocytosis of Delta and transendocytosis of the Notch extracellular domain by the signaling cell. This facilitates intramembranous cleavage of the remaining Notch receptor, release of the Notch intracellular fragment, and activation of target genes in neighboring cells.
由Notch信号介导的侧向抑制导致在原神经基因表达所定义的区域内选择允许成为神经元的细胞。斑马鱼mib突变体胚胎中侧向抑制的减弱使得过多的神经祖细胞分化为神经元。mib的定位克隆表明它是Notch信号通路中的一个基因，编码一种环状泛素连接酶。Mib与Delta的胞内结构域相互作用，促进其泛素化和内化。细胞移植研究表明，mib功能对于信号细胞中Notch在邻近细胞中的有效激活至关重要。这些观察结果支持了一种Notch激活模型，即Delta-Notch相互作用之后是Delta的内吞作用以及信号细胞对Notch胞外结构域的跨细胞内吞作用。这有助于剩余Notch受体的膜内裂解、Notch胞内片段的释放以及邻近细胞中靶基因的激活。
