The tripartite motif proteins TRIM-2 and TRIM-3 have been put forward as putative organizers of neuronal outgrowth and structural plasticity. Here, we identified a molluscan orthologue of TRIM-2/3, named L-TRIM, which is up-regulated during in vitro neurite outgrowth of central neurons. In adult animals, L-Trim mRNA is ubiquitously expressed at low levels in the central nervous system and in peripheral tissues. Central nervous system expression of L-Trim mRNA is increased during postnatal brain development and during in vitro and in vivo neuronal regeneration. In vitro double-stranded RNA knock-down of L-Trim mRNA resulted in a >70% inhibition of neurite outgrowth. Together, our data establish a crucial role for L-TRIM in developmental neurite outgrowth and functional neuronal regeneration and indicate that TRIM-2/3 family members may have evolutionary conserved functions in neuronal differentiation. © 2005 Elsevier Inc. All rights reserved.