Zhu, XL (reprint author), Chinese Acad Sci, Mol Cell Biol Lab, Inst Biochem & Cell Biol, 320 Yue Yang Rd, Shanghai 200031, Peoples R China,email@example.com
Lis1 is an essential protein whose insufficiency causes aberrant neuronal positioning during neocortical development. It is believed to regulate both cytoplasmic dynein, a microtubule minus-end-directed motor, through direct interaction, and platelet-activating factor acetylhydrolase (PAF-AH) Ib by complexing with the catalytic subunits alpha 1 and alpha 2. Although alpha 1 and alpha 2 are highly expressed in brain, their deficiencies fail to cause brain abnormality. Here, we show that overexpression of alpha 2 or alpha 1 results in inactivation of dynein characterized by Golgi and endosome dispersion and mitotic delay. Further overexpression of Lis1 or Ndel1, a Lis1- and dynein-binding protein that is also crucial for dynein function, restored Golgi and endosome distribution. Biochemical assays showed that alpha 1 and especially alpha 2, were able to compete against Ndel1 and dynein for Lis1 binding in a dose-dependent manner. Overexpression of alpha 2 in developing rat brain repressed the radial migration of neurons and mitotic progression of neuroprogenitors. By contrast, a Lis1-binding-defective point mutant, alpha 2(E39D), was ineffective in the above assays. These results indicate an antagonistic effect of alpha 1, alpha 2 and Ndel1 for Lis1 binding, probably to modulate dynein functions in vivo. They also help to explain why brain development is particularly sensitive to a decrease in Lis1 levels.
Ding, Chong; Liang, Xujun; Ma, Li; Yuan, Xiaobing; Zhu, Xueliang.Opposing effects of Ndel1 and alpha 1 or alpha 2 on cytoplasmic dynein through competitive binding to Lis1,JOURNAL OF CELL SCIENCE,2009,122(16):2820-2827