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.Neurite outgrowth and maturation are critical for development of the nervous system determining neuronal connectivity. Neurite outgrowth/maturation is stimulated by extracellular signals, including neurotrophins and electrical activity. In forebrain neurons, the neurotrophin BDNF and/or neuronal electrical activity stimulates morphogenesis of the postsynaptic neurites (dendrites) by activation of several signaling pathways, including calcium/calmodulin-dependent protein kinase (CaMK) 2 I/II/IV, ERK1/2 (extracellular signal-regulated kinase-1/2), and PI3K (phosphatidylinositol 3-kinase)/mTOR (mammalian target of rapamycin). Rapid regulation of cytoskeletal dynamics and/or long-term changes in gene expression programs have been implicated as pro-neuritic effector mechanisms for these signaling mediators (1-3). The CaMK/ ERK-regulated transcription factor cAMP response elementbinding protein (CREB) is critical for neuritogenesis stimulated by electrical activity (4 -6). Although BDNF has been recognized as one of the most important drivers of neurite outgrowth (1, 2), the BDNF-activated pro-neuritic transcription factors, as well as their target genes, remain to be identified.The nucleolus is a structure within the nucleus that contains hundreds of clustered repeats of 45 S rRNA genes (rDNA) whose primary 45 S transcript is rapidly processed, producing 5.8, 18, and 28 S rRNAs (7,8). Transcription of rDNA is mediated by RNA polymerase-1 (Pol1), initiating the nucleolus-based process of ribosomal biogenesis. Nucleolar transcription is tightly regulated to adjust ribosomal production to cellular needs. For instance, growth factors stimulate Pol1 by the ERK1/2 pathway-mediated phosphoryl...