title: Non-muscle myosin II regulates neuronal actin dynamics by interacting with guanine nucleotide exchange factors.
abstract: BACKGROUND
  Non-muscle myosin II (NM II) regulates a wide range of cellular functions, including neuronal differentiation, which requires precise spatio-temporal activation of Rho GTPases. The molecular mechanism underlying the NM II-mediated activation of Rho GTPases is poorly understood. The present study explored the possibility that NM II regulates neuronal differentiation, particularly morphological changes in growth cones and the distal axon, through guanine nucleotide exchange factors (GEFs) of the Dbl family.
  
  
  RESULTS
  NM II colocalized with GEFs, such as βPIX, kalirin and intersectin, in growth cones. Inactivation of NM II by blebbistatin (BBS) led to the increased formation of short and thick filopodial actin structures at the periphery of growth cones. In line with these observations, FRET analysis revealed enhanced Cdc42 activity in BBS-treated growth cones. BBS treatment also induced aberrant targeting of various GEFs to the distal axon where GEFs were seldom observed under physiological conditions. As a result, numerous protrusions and branches were generated on the shaft of the distal axon. The disruption of the NM II-GEF interactions by overexpression of the DH domains of βPIX or Tiam1, or by βPIX depletion with specific siRNAs inhibited growth cone formation and induced slender axons concomitant with multiple branches in cultured hippocampal neurons. Finally, stimulation with nerve growth factor induced transient dissociation of the NM II-GEF complex, which was closely correlated with the kinetics of Cdc42 and Rac1 activation.
  
  
  CONCLUSIONS
  Our results suggest that NM II maintains proper morphology of neuronal growth cones and the distal axon by regulating actin dynamics through the GEF-Rho GTPase signaling pathway.
authors.affiliation: Department of Biochemistry, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk, Korea.
authors.forename: Eun-Young
authors.initials: EY
authors.lastname: Shin
authors.affiliation: Division of Hazardous Substances Analysis, Daejeon Regional Food and Drug Administration, Daejeon, Chungnam, Korea.
authors.forename: Chan-Soo
authors.initials: CS
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk, Korea.
authors.forename: Cheong-Yong
authors.initials: CY
authors.lastname: Yun
authors.affiliation: Department of Biochemistry, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk, Korea.
authors.forename: So-Yoon
authors.initials: SY
authors.lastname: Won
authors.affiliation: Department of Microbiology, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk, Korea.
authors.forename: Hyong-Kyu
authors.initials: HK
authors.lastname: Kim
authors.affiliation: Department of Biochemistry, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk, Korea.
authors.forename: Yong Hee
authors.initials: YH
authors.lastname: Lee
authors.affiliation: Department of Biochemistry, College of Medicine, Dankook University, Cheonan, Chungnam, Korea.
authors.forename: Sahng-June
authors.initials: SJ
authors.lastname: Kwak
authors.affiliation: Department of Biochemistry, College of Medicine and Medical Research Institute, Chungbuk National University, Cheongju, Chungbuk, Korea.
authors.forename: Eung-Gook
authors.initials: EG
authors.lastname: Kim
mesh_terms: D000199:Actins / Q000378:metabolism*; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000378:metabolism; D002478:Cells, Cultured; D005260:Female; D020439:Growth Cones / Q000187:drug effects / Q000378:metabolism; D006576:Heterocyclic Compounds, 4 or More Rings / Q000494:pharmacology; D006624:Hippocampus / Q000166:cytology; D008954:Models, Biological; D009414:Nerve Growth Factors / Q000378:metabolism; D016501:Neurites / Q000187:drug effects / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism*; D024501:Nonmuscle Myosin Type IIB / Q000378:metabolism*; D011485:Protein Binding / Q000187:drug effects; D017434:Protein Structure, Tertiary; D011554:Pseudopodia / Q000187:drug effects / Q000378:metabolism; D017207:Rats, Sprague-Dawley; D064067:Rho Guanine Nucleotide Exchange Factors / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism; D054462:p21-Activated Kinases / Q000378:metabolism; D020830:rac1 GTP-Binding Protein / Q000378:metabolism
chemical_list: D000199:Actins; D006576:Heterocyclic Compounds, 4 or More Rings; D009414:Nerve Growth Factors; D064067:Rho Guanine Nucleotide Exchange Factors; C472645:blebbistatin; D054462:p21-Activated Kinases; D024501:Nonmuscle Myosin Type IIB; D020764:cdc42 GTP-Binding Protein; D020830:rac1 GTP-Binding Protein
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