title: RNA polymerase 1-driven transcription as a mediator of BDNF-induced neurite outgrowth.
abstract: Neurite outgrowth is essential for development of the nervous system. Neurotrophins including BDNF are among extracellular signals that regulate neurite outgrowth. The ERK1/2 pathway contributes to intracellular signaling networks transducing the pro-neuritic effects of BDNF. In the nucleolus, RNA polymerase-1 (Pol1)-mediated transcription regulates ribosomal biogenesis, enabling cellular protein synthesis and growth. Hence, we tested the possibility that Pol1 is an effector for pro-neuritic signals such as BDNF. We report that Pol1-mediated nucleolar transcription was increased by BDNF in an ERK1/2-dependent manner in rat forebrain neurons. Conversely, in cultured hippocampal neurons, knockdown of a Pol1 coactivator, transcription initiation factor 1A (TIF1A), attenuated BDNF- or ERK1/2-induced neurite outgrowth. Also, upon overexpression, a constitutively active mutant of TIF1A strongly promoted neurite outgrowth, including increases in total neurite length and branching. Finally, overexpression of wild-type TIF1A enhanced the pro-neuritic effects of ERK1/2 activation. These observations indicate that the Pol1-mediated nucleolar transcription regulates neurite outgrowth and serves as a major pro-neuritic effector of the BDNF-activated ERK1/2 pathway. Thus, development of the nervous system appears critically dependent on the nucleolus.
authors.affiliation: Department of Neurological Surgery, University of Louisville, Kentucky Spinal Cord Injury Research Center, Louisville, Kentucky 40292, USA.
authors.forename: Cynthia
authors.initials: C
authors.lastname: Gomes
authors.forename: Scott C
authors.initials: SC
authors.lastname: Smith
authors.forename: Mark N
authors.initials: MN
authors.lastname: Youssef
authors.forename: Jing-Juan
authors.initials: JJ
authors.lastname: Zheng
authors.forename: Theo
authors.initials: T
authors.lastname: Hagg
authors.forename: Michal
authors.initials: M
authors.lastname: Hetman
mesh_terms: D000818:Animals; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism* / Q000494:pharmacology; D002466:Cell Nucleolus / Q000235:genetics / Q000378:metabolism*; D002478:Cells, Cultured; D004789:Enzyme Activation / Q000187:drug effects / Q000502:physiology; D006624:Hippocampus / Q000166:cytology / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects / Q000502:physiology*; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D016501:Neurites / Q000378:metabolism*; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D016548:Prosencephalon / Q000166:cytology / Q000378:metabolism; D012318:RNA Polymerase I / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology*
chemical_list: D019208:Brain-Derived Neurotrophic Factor; D009687:Nuclear Proteins; D014157:Transcription Factors; C093517:transcriptional intermediary factor 1; D048052:Mitogen-Activated Protein Kinase 3; D012318:RNA Polymerase I