12-P002 The E3 ubiquitin ligase Arkadia2C regulates BMP signalling in motor neuron development

Vertebrate neurotrophins (NTs: NGF, BDNF, NT3, NT4) form a family of signalling molecules with key functions in nervous system development and function. They regulate cell survival, axon guidance and targeting, synaptic formation and function, learning and memory. Deficient NGF function occurs in Alzheimer’s disease and alterations in BDNF function underlie psychiatric and cognitive disorders such as epilepsy, autism, anxiety and depression. NTs are therapeutic targets in pain control (e.g. chronic pain in cancer). We recently reported that a family of Drosophila neurotrophins (DNTs) formed by DNT1, DNT2 and Spz regulate neuronal survival and targeting in fruit-flies (Zhu et al., 2008 PLoS Biology 6, e284). We are now investigating the roles that DNTs play in neuronal function, using both loss and gain of function conditions for each of the DNTs. Here, we report the involvement of DNTs in synapse formation and in adult locomotion. With the help of mathematical algorithms that we have developed, we quantify automatically and objectively phenotypic changes in: (i) the number of boutons and active zones at the larval neuromuscular junction (NMJ) synapse; (ii) axon terminal length and branch number at the NMJ; (iii) and speed and trajectory of adult flies in a locomotion paradigm. Using genetic rescue experiments, we investigate functional redundancy and whether the DNTs are required in muscle or neurons. Our findings suggest that neuronal functions of NTs are evolutionarily conserved, supporting the notion that NTs underlie multiple aspects of nervous system development and function in all animals with a CNS and brain.