The growth of organs, cells and subcellular structures must be coordinated during development to produce a proportional and functional organism. However, the mechanisms that control scaling growth at the subcellular level are not well understood. This process is especially important in the nervous system, where incorrect matching of synapse size to target size can result in neurodevelopmental disorders. This proposal will use Drosophila neuromuscular synapses, which undergo extensive growth during larval development, as a model system to understand scaling growth. Increasing or decreasing the size of the target muscle by cell-autonomous changes in the Insulin Receptor signaling pathway results in proportional changes in the size of the synapse, maintaining a constant ratio of synapse size to muscle size. Altering the size of a single muscle specifically affects the synapses on that muscle, implying a local signaling mechanism that does not rely on circulating hormones or changes in developmental timing.
The first aim of this proposal is to identify signals that communicate muscle growth status to motor neuron terminals. Comparing the effects of different components of the Insulin Receptor pathway revealed separate contributions mediated by the membrane lipid phosphatidylinositol (3,4,5)-triphosphate and the protein kinase Akt. Candidate effectors of phosphatidylinositol (3,4,5)-triphosphate will be evaluated for their role in scaling growth, and a genetic screen will be used to identify transmembrane or secreted molecules involved in transmitting one or both signals.
The second aim will use live imaging to better characterize the process of developmental synapse growth and compare it to growth induced by neuronal activity. These experiments will distinguish whether addition of new boutons requires local accumulation of muscle synaptic components, or whether the muscle provides a more diffuse signal that increases the probability of bouton formation. Elucidating the mechanism by which developmental growth is communicated from postsynaptic to presynaptic cells may provide insight into disorders such as autism and schizophrenia, in addition to providing a more basic framework to understand scaling growth in general.
As organisms develop, their constituent parts must grow at similar rates to achieve the correct proportions. We propose to investigate how cells communicate their growth status to each other, using the regulation of motor neuron synapse size by the size of the target muscle as a model system. Identifying the signals used to convey growth information will advance our understanding of neurodevelopmental disorders in which synapse size is abnormal.
