Dendrite morphogenesis is regulated by neuronal activity or neurotrophins, which may function by activating intrinsic signaling proteins, including Rho family GTPases. Here we report that activity-and brain-derived neurotrophic factor (BDNF)-dependent dendritic morphogenesis requires activation of geranylgeranyltransferase I (GGT), a prenyltransferase that mediates lipid modification of Rho GTPases. Dendritic arborization in cultured hippocampal neurons was promoted by over-expression of GGT, and reduced by inhibition or down-regulation of GGT. Furthermore, GGT was activated by neuronal depolarization or BDNF, both of which promote dendritic arborization, in cultured hippocampal neurons. Moreover, exploration of a novel environment caused activation of GGT in the mice hippocampus, suggesting that neural activity activates GGT in vivo. Interestingly, GGT was physically associated with tropomyosin-related kinase B (TrkB), the receptor for BDNF, and this association was enhanced by depolarization. Disrupting the GGT-TrkB interaction or down-regulating GGT activity attenuated depolarization-or BDNF-induced dendrite development. Finally, the GGT effect on dendrite arborization was prevented by over-expressing Rac1 with the prenylation site deleted or mutated. Thus depolarization-or BDNF-dependent dendrite development may be mediated by GGT-induced prenylation of Rho GTPases.BDNF ͉ dendrite ͉ neuronal activity ͉ Rac ͉ prenylation D endritic morphogenesis is a critical step for establishing neural circuits. The growth and branching of dendritic arbors are controlled by both external signals and intracellular pathways (1, 2). Neuronal activity and neurotrophins, such as brain-derived neurotrophic factor (BDNF) and neurotrophin-3, are known to regulate dendrite development through multiple signaling pathways, leading to cytoskeletal reorganization or gene expression required for dendritic growth (2-7). For example, members of the Rho family of small GTPases, including Rac1, Cdc42, and RhoA, are important for distinct aspects of dendrite development by modulating actin cytoskeleton (8, 9). Activation of Rho A attenuates dendrite growth and branching, whereas activation of Rac1 facilitates dendrite growth (8, 10, 11). Importantly, dendrite growth increased by visual activity requires Rho GTPases (12) and BDNF-dependent dendritic growth may be mediated by Rac1 (13). Thus, Rho GTPase may mediate the effects of BDNF or neuronal activity on dendrite development. However, the mechanism by which BDNF and activity regulate Rho GTPases remains largely unknown.The Rho GTPase cycles between a GTP-bound active state and a GDP-bound inactive state, and this process is regulated by GTPase activating proteins and guanine nucleotide exchange factors (GEFs) (14, 15). Importantly, GTPases need to be translocated from the cytosol to the membrane for their activation (16,17). This is achieved by prenylation, a reaction mainly catalyzed by farnesyltransferase (FT) or geranylgeranyltransferase I (GGT), which acts to covalently couple a lipid m...