BMP gradients steer nerve growth cones by a balancing act of LIM kinase and Slingshot phosphatase on ADF/cofilin.
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.
Wen
Zhexing
Z
Department of Neuroscience and Cell Biology, University of Medicine and Dentistry of New Jersey, Robert Wood Johnson Medical School, Piscataway, NJ 08854, USA.
Han
Liang
L
Bamburg
James R
JR
Shim
Sangwoo
S
Ming
Guo-li
GL
Zheng
James Q
JQ
D000818:Animals; D001757:Blastomeres / Q000378:metabolism; D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D051338:Cofilin 1 / Q000378:metabolism*; D051345:Destrin / Q000235:genetics / Q000378:metabolism*; D004625:Embryo, Nonmammalian; D005727:Ganglia, Spinal / Q000166:cytology; D020439:Growth Cones / Q000502:physiology*; D054461:Lim Kinases; D008845:Microinjections; D008954:Models, Biological; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism*; D011494:Protein Kinases / Q000378:metabolism*; D012333:RNA, Messenger / Q000008:administration & dosage; D050052:TRPC Cation Channels / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism*; D014981:Xenopus / Q000196:embryology; D029867:Xenopus Proteins / Q000378:metabolism
D055419:Bone Morphogenetic Protein 7; D019485:Bone Morphogenetic Proteins; D051338:Cofilin 1; D051345:Destrin; D012333:RNA, Messenger; D050052:TRPC Cation Channels; C502469:TRPC1 protein, Xenopus; D016212:Transforming Growth Factor beta; D029867:Xenopus Proteins; C525822:bmp7.1 protein, Xenopus; D011494:Protein Kinases; D054461:Lim Kinases; D010744:Phosphoric Monoester Hydrolases; D002118:Calcium