Grant: Project Grant

How neurons maintain structural and physiological stability of synapses (contact points) is poorly understood, even though synaptic degeneration is an established hallmark of most neurological disorders. An important clue has come from work in the fruit fly, Drosophila, which revealed that bone morphogenetic proteins (BMPs) secreted from muscle activate BMP signaling in motor neurons. Loss of BMP signaling (or BMP regulated gene expression) in motor neurons severely destabilizes synaptic morphology and reduces neurotransmission. Follow up work confirmed that BMPs play the same role in mammalian motor neurons, and disrupted BMP signaling has become implicated in motor neuron diseases such as ALS. It is now clear that BMP signaling controls a battery of novel genes required for morphological and physiological stability of motor neuron synapses (and other synapses) from Drosophila to humans. Most of these genes have not been identified. Our preliminary data has taken the first important step by identifying all BMP regulated genes in fly neurons (by RNAseq). With these in hand, this project can now address two, important knowledge gaps: 1) How does BMP signaling control those genes' expression? We will determine which transcription factors, resident in motor neurons, enable the BMP pathway to control gene expression in motor neurons. 2) What is the function of those genes? We will determine the function of ~100 of these novel genes that we postulate play novel conserved roles in synaptic stability of morphology and neurotransmission in humans. We address these questions in Drosophila. The mechanisms under examination are extremely well conserved from Drosophila to humans, and Drosophila offers the only genetic toolset able to complete these goals in 5 years. As this project will reveal how a novel gene network is regulated and deployed to control synaptic stability, our work will revolutionize our ability to combat synaptic degeneration in neurological disorder