title: Brain-derived neurotrophic factor promotes vesicular glutamate transporter 3 expression and neurite outgrowth of dorsal root ganglion neurons through the activation of the transcription factors Etv4 and Etv5.
abstract: Brain-derived neurotrophic factor (BDNF) is critical for sensory neuron survival and is necessary for vesicular glutamate transporter 3 (VGLUT3) expression. Whether the transcription factors Etv4 and Etv5 are involved in these BDNF-induced effects remains unclear. In the present study, primary cultured dorsal root ganglion (DRG) neurons were used to test the link between BDNF and transcription factors Etv4 and Etv5 on VGLUT3 expression and neurite outgrowth. BDNF promoted the mRNA and protein expression of Etv4 and Etv5 in DRG neurons. These effects were blocked by extracellular signal-regulated protein kinase 1/2 (ERK1/2) inhibitor PD98059 but not phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 or phospholipase C-γ (PLC-γ) inhibitor U73122. Etv4 siRNA and Etv5 siRNA effectively blocked the VGLUT3 expression and neurite elongation induced by BNDF. The overexpression of Etv4 or Etv5 potentiated the effects of BNDF-induced neurite elongation and growth-associated protein 43 (GAP-43), medium neurofilament (NF-M), and light neurofilament (NF-L) expression while these effects could be inhibited by Etv4 and Etv5 siRNA. These data imply that Etv4 and Etv5 are essential transcription factors in modulating BDNF/TrkB signaling-mediated VGLUT3 expression and neurite outgrowth. BDNF, through the ERK1/2 signaling pathway, activates Etv4 and Etv5 to initiate GAP-43 expression, promote neurofilament (NF) protein expression, induce neurite outgrowth, and mediate VGLUT3 expression for neuronal function improvement. The biological effects initiated by BDNF/TrkB signaling linked to E26 transformation-specific (ETS) transcription factors are important to elucidate neuronal differentiation, axonal regeneration, and repair in various pathological states.
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan 250012, China. Electronic address: cyyzld@163.com.
authors.forename: Dong
authors.initials: D
authors.lastname: Liu
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan 250012, China. Electronic address: zhen@sdu.edu.cn.
authors.forename: Zhen
authors.initials: Z
authors.lastname: Liu
authors.affiliation: Department of Rheumatology, Shandong University Qilu Hospital, Jinan 250012, China. Electronic address: huaxiangliu@hotmail.com.
authors.forename: Huaxiang
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Orthopaedics, Shandong University Qilu Hospital, Jinan 250012, China. Electronic address: lihao462929@163.com.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.affiliation: Department of Otolaryngology, Shandong University Qilu Hospital, Jinan 250012, China. Electronic address: 13606371129@163.com.
authors.forename: Xinliang
authors.initials: X
authors.lastname: Pan
authors.affiliation: Department of Anatomy, Shandong University School of Medicine, Jinan 250012, China. Electronic address: zli@sdu.edu.cn.
authors.forename: Zhenzhong
authors.initials: Z
authors.lastname: Li
mesh_terms: D000818:Animals; D000831:Animals, Newborn; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D002478:Cells, Cultured; D002867:Chromones / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D019922:GAP-43 Protein / Q000378:metabolism; D005727:Ganglia, Spinal / Q000166:cytology*; D005786:Gene Expression Regulation / Q000187:drug effects; D020935:MAP Kinase Signaling System / Q000187:drug effects; D009025:Morpholines / Q000494:pharmacology; D000071446:Neuronal Outgrowth / Q000187:drug effects*; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D018709:Statistics, Nonparametric; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D050496:Vesicular Glutamate Transport Proteins / Q000378:metabolism*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D002867:Chromones; D004268:DNA-Binding Proteins; C510951:ETV4 protein, rat; D004791:Enzyme Inhibitors; C513243:Etv5 protein, rat; D005419:Flavonoids; D019922:GAP-43 Protein; D009025:Morpholines; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C482103:Slc17a8 protein, rat; D015534:Trans-Activators; D014157:Transcription Factors; D050496:Vesicular Glutamate Transport Proteins; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one
keywords: Brain-derived neurotrophic factor; Dorsal root ganglion; Etv4; Etv5; Neurite outgrowth; Vesicular glutamate transporter 3