Activin A is a multifunctional homo-dimeric protein that belongs to the transforming growth factor (TGE)-beta superfamily In neurons. activin has neuroprotective effects both in vitro and in vivo, but it inhibits neuronal differentiation in some cell lines Here we report that activin A can promote neuronal differentiation in particular cases We examined activin A-induced neuronal differentiation and survival in a selected subpopulation of a human neuroblastoma cell line, SK-N-SH, grown in low-serum (differentiation-inducing) conditions Activin A caused dramatic neurite outgrowth, and increased the expression of neuronal markers and the transactivation of dopamine beta-hydroxylase We demonstrated that the activin A signal is transduced through the activin A type 1 receptor, ALK4, and transactivates several TGF-beta target genes in a SMAD-independent manner That is, activin A did not induce the phosphorylation of SMAD2/3, the interaction of SMAD2/3 with SMAD4, the binding of SMAD2/3 to the promoter of TGF-beta target genes, or the accumulation of SMAD2/3 in the nucleus. These results suggest that, in particular cases, activin A can induce neuronal differentiation and support neuronal survival in vitro These findings may reflect previously unknown functions of activin A in neuronal cells in vivo (C) 2010 Elsevier Inc. All rights reserved