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J. Cell Biol. 178 (1): 107-119

Copyright © 2007 by the Rockefeller University Press.

Article

BMP gradients steer nerve growth cones by a balancing act of LIM kinase and Slingshot phosphatase on ADF/cofilin

Zhexing Wen1, Liang Han1, James R. Bamburg2,3, Sangwoo Shim4, Guo-li Ming4, , and James Q. Zheng1

1 Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854
2 Department of Biochemistry and Molecular Biology and 3 Molecular, Cellular, and Integrative Neuroscience Program, Colorado State University, Fort Collins, CO 80523
4 Institute for Cell Engineering, Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD 21205

Correspondence to James Q. Zheng: james.zheng{at}umdnj.edu

Abstract: Bone morphogenic proteins (BMPs) are involved in axon pathfinding, but how they guide growth cones remains elusive. In this study, we report that a BMP7 gradient elicits bidirectional turning responses from nerve growth cones by acting through LIM kinase (LIMK) and Slingshot (SSH) phosphatase to regulate actin-depolymerizing factor (ADF)/cofilin-mediated actin dynamics. Xenopus laevis growth cones from 4–8-h cultured neurons are attracted to BMP7 gradients but become repelled by BMP7 after overnight culture. The attraction and repulsion are mediated by LIMK and SSH, respectively, which oppositely regulate the phosphorylation-dependent asymmetric activity of ADF/cofilin to control the actin dynamics and growth cone steering. The attraction to repulsion switching requires the expression of a transient receptor potential (TRP) channel TRPC1 and involves Ca2+ signaling through calcineurin phosphatase for SSH activation and growth cone repulsion. Together, we show that spatial regulation of ADF/cofilin activity controls the directional responses of the growth cone to BMP7, and Ca2+ influx through TRPC tilts the LIMK-SSH balance toward SSH-mediated repulsion.

Z. Wen and L. Han contributed equally to this paper.

Abbreviations used in this paper: ADF, actin-depolymerizing factor; ANOVA, analysis of variance; BMP, Bone Morphogenic Protein; CaN, calcineurin; DN, dominant negative; DTAF, 5-(4,6-dichlorotriazinyl)aminofluorescein; IF, immunofluorescence; LIMK, LIM kinase; p-XAC, phosphorylated XAC; SFM, serum-free medium; SSH, Slingshot; TRP, transient receptor potential; WT, wild type; XAC, Xenopus ADF/cofilin.

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