The long-term goal of our research project is to define mechanisms involved in regulating the formation, maintenance, and maturation of pre- and postsynaptic elements of the neuromuscular junction (NMJ). The NMJ is the chemical synaptic connection between motor neuron and skeletal muscle. The NMJ is essential for routine activities such as breathing, swallowing, and movement. We investigate the NMJ as a model for understanding synapses because the NMJ can provide information pertinent to both peripheral and central synapses, while its relatively simple structure and easy accessibility make it more amenable to investigation than the central synapse. This project addresses a fundamental question in the interaction between the pre- and postsynaptic elements of the NMJ – how muscle talks back to the nerve to establish and maintain normal synapses. Using genetic approaches in mice, we found that the muscle dihydropyridine receptors – which are known for their roles in muscle contraction – plays a crucial regulatory role in the differentiation of the motor nerve terminals and NMJ formation. This finding was unexpected, in part because much of the information known about the regulation of the pre-synaptic development point to a predominantly “neurocentric paradigm.” The discovery of an important muscle-derived regulator suggests that muscle plays a much more active role in regulating presynaptic elements than was previously believed. Our preliminary findings open a new avenue of investigation for identifying feed back mechanisms from muscle to nerve. By identifying these regulatory signals, we will be able to provide new targets for the development of therapeutic strategies to treat or prevent neurodevelopmental disorders and neurodegenerative diseases.