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First published online 21 July 2009
doi: 10.1242/jcs.048777

Journal of Cell Science 122, 2820-2827 (2009)
Published by The Company of Biologists 2009
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Research Article

Opposing effects of Ndel1 and {alpha}1 or {alpha}2 on cytoplasmic dynein through competitive binding to Lis1

Chong Ding1, Xujun Liang2, Li Ma1, Xiaobing Yuan2 and Xueliang Zhu1,*

1 Laboratory of Molecular Cell Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China
2 State Key Laboratory of Neurobiology, Institute of Neuroscience, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue Yang Road, Shanghai 200031, China

* Author for correspondence (xlzhu{at}sibs.ac.cn)

Accepted 26 May 2009

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}2E39D, 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.

Key words: Nudel, Cytoplasmic dynein, Mitosis, Neuronal migration, Platelet-activating factor acetylhydrolase (PAF-AH) Ib complex, Vesicle transport


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