The mechanisms that control the formation and maintenance of accurate and functional synaptic connections are vital to the operation of the nervous system. While much remains to be learned about the molecular machinery underlying the specific directional growth of axons to reach target cells and the formation of synapses in the developing and regenerating nervous system, many of the genes needed for these events have been identified. This foundation of knowledge provides an opportunity to better understand the mechanisms that regulate the deployment of this molecular arsenal during normal development, or in disease states that compromise the function or survival of neural circuits. Multiple levels of regulatory mechanisms exist, from transcriptional to post-transcriptional and translational control of neural gene expression. Our interest is to better define such regulatory strategies.
Spinal muscular atrophy (SMA), a common genetic cause of infant death, is a devastating neurodegenerative disorder causing progressive loss of motor function due to malfunction of neuromuscular junctions (NMJs) and eventual death of motor neurons. SMA is caused by loss of Survival Motor Neuron (SMN1) gene, a component of the SMN complex involved in assembly of the small nuclear ribonucleoproteins that recognize and remove introns from pre-mRNA. SMN is thought to control the synthesis and the delivery of key synaptic proteins and mRNAs, although additional motor neuron specific functions are suspected. Thus, dissecting molecular circuit underlying the SMA neuropathology allows us to address outstanding questions of control the formation and maintenance of neural networks.
However, the identity of functionally relevant SMN target genes and the precise molecular role of SMN in nervous system and at the NMJ remain unknown. We employ SMA disease model developed in Drosophila, a powerful genetic model organism with well-conserved neuronal cell biology, and examine in what manner the reduction of SMN leads motor neurons loss. As previous screening to find genetic interactor of SMN demonstrated that alternation of components in two well characterized signaling pathways can either ameliorate or deteriorate phenotypes associated with SMN reduction, we will analyze the interaction between SMN and those signaling pathways in the formation and maintenance of the neuromuscular network. Furthermore, our long-term goal is to identify molecular circuit in which SMN integrated intervenes during establishment and maintenance of neuromuscular connection by using state-of-the-art sequencing technology available at OIST.