Postsynaptic Ca(V)1.1-driven calcium signaling coordinates presynaptic differentiation at the developing neuromuscular junction

Proper formation of neuromuscular synapses requires the reciprocal communication between motor neurons and muscle cells. Several anterograde and retrograde signals involved in neuromuscular junction formation are known. However the postsynaptic mechanisms regulating presynaptic differentiation are still incompletely understood. Here we report that the skeletal muscle calcium channel (Ca(V)1.1) is required for motor nerve differentiation and that the mechanism by which Ca(V)1.1 controls presynaptic differentiation utilizes activity-dependent calcium signaling in muscle. In mice lacking Ca(V)1.1 or Ca(V)1.1-driven calcium signaling motor nerves are ectopically located and aberrantly defasciculated. Axons fail to recognize their postsynaptic target structures and synaptic vesicles and active zones fail to correctly accumulate at the nerve terminals opposite AChR clusters. These presynaptic defects are independent of aberrant AChR patterning and more sensitive to deficient calcium signals. Thus, our results identify Ca(V)1.1-driven calcium signaling in muscle as a major regulator coordinating multiple aspects of presynaptic differentiation at the neuromuscular synapse.