Phylogenesis of brain-derived neurotrophic factor (BDNF) in vertebrates.

Brain-derived neurotrophic factor (BDNF) belongs to neurotrophin family, a class of molecules playing key roles in neuronal development, survival and regeneration, neurite growth and plasticity: memory processes are mainly affected, and mutations of the human BDNF gene are associated to cognitive and behavioural disturbances. All neurotrophins contain a highly conserved C-terminal domain and bind to the same receptor family. Both correct folding and post-translational processing of the entire preproprotein are pivotal for sorting to the extracellular space, dimerization and receptor binding. Evolutionary studies conducted so far demonstrate that a single ancestor gene underwent two independent duplication events at an early stage of vertebrate evolution, leading to the formation of the current neurotrophins. However, works focusing on BDNF evolution are scarce and fragmentary, mainly in lower vertebrates. In this work, we report cloning of eight DNA sequences from amphibians and teleosts, and analysis of the entire coding regions (cDNA sequences) of BDNF from 35 organisms, from teleosts to mammals. A phylogenetic tree was constructed and the analysis of non-synonymous-synonymous substitution rates performed for the different branches. Our results suggest that natural selection is acting on mammals, separating them from other classes. Since preproprotein cleavage and 3D structure of mature protein are important for functional activity of BDNF, we also propose a de novo prediction of the 3D structure of translates in at least one species for each class, in order to get hints about the functional constraints of the protein.