Drosophila Neurotrophins Reveal a Common Mechanism for Nervous System Formation

Abstract

Neurotrophic interactions occur in Drosophila, but to date, no neurotrophic factor had been found. Neurotrophins are the main vertebrate secreted signalling molecules that link nervous system structure and function: they regulate neuronal survival, targeting, synaptic plasticity, memory and cognition. We have identified a neurotrophic factor in flies, Drosophila Neurotrophin (DNT1), structurally related to all known neurotrophins and highly conserved in insects. By investigating with genetics the consequences of removing DNT1 or adding it in excess, we show that DNT1 maintains neuronal survival, as more neurons die in DNT1 mutants and expression of DNT1 rescues naturally occurring cell death, and it enables targeting by motor neurons. We show that Spätzle and a further fly neurotrophin superfamily member, DNT2, also have neurotrophic functions in flies. Our findings imply that most likely a neurotrophin was present in the common ancestor of all bilateral organisms, giving rise to invertebrate and vertebrate neurotrophins through gene or whole-genome duplications. This work provides a missing link between aspects of neuronal function in flies and vertebrates, and it opens the opportunity to use Drosophila to investigate further aspects of neurotrophin function and to model related diseases.

Programmed Cell Death in Neurodevelopment

“…The most notable example of cell number regulation by cell death is described by the neurotrophic theory, as mentioned in introduction ( Figure 4H) (Cowan, 2001;Levi-Montalcini, 1987;Oppenheim, 1991;Purves et al, 1988;Raff, 1992). This mechanism serves as a means of quantitative matching of not only neurons and glia with targets and afferents in vertebrates, but also in the Drosophila (Barres et al, 1992;Bergmann et al, 2002;Buss et al, 2006;Hidalgo et al, 2001;Zhu et al, 2008). The determination of cell viability versus death depends on the amount of neurotrophins and the timing of their reception in target tissue, as mediated by the dependence receptor system, as extensively discussed in many excellent reviews on neurotrophic theory and dependence receptors (Buss et al, 2006;Dekkers et al, 2013;Jiang and Reichert, 2012).…”

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

“…Evolutionary studies on neurotrophins conducted so far demonstrate that two independent duplication events of a single ancestor gene occurred at an early stage of vertebrate evolution, leading to the formation of the current neurotrophins (Hallböök, 1999). The recent discovery of a putative neurotrophin-Trk system after Strongylocentrotus purpuratus genome analysis (Burke et al, 2006) and the characterization of Trk homologs in Invertebrates such as Lymnea stagnalis (Van Kesteren et al, 1998) and amphioxus (Benito-Gutiérrez et al, 2005) led to the hypothesis that the neurotrophin/Trk signalling system could have been present in the common ancestor of protostomes and deuterostomes (Hallböök et al, 2006); thus, the neurotrophin/Trk signalling system would not be a vertebrate innovation, as partially confirmed by the structural and functional investigation on DNT1, a neurotrophin present in Drosophila melanogaster (Zhu et al, 2008).…”

Molecular Mechanism That Induces Activation of Spätzle, the Ligand for the Drosophila Toll Receptor

“…This putative ␣-helix is highly conserved in Spätzle homologues from distantly related species such as Drosophila virilis, Manduca sexta (22) and the mosquito Anopheles gambiae (Fig. 6B) but not in paralogues such as the Drosophila DNT1 (Spz2) (23,24) or the vertebrate neurotrophins (25).…”