C3 and CD47 mediate sensory-motor circuit refinement during spinal cord development

Overground movement in mammals requires the assembly and refinement of sensory-motor circuits to ensure proper motor control. Although, supernumerary synapses are formed and subsequently pruned in the brain, whether this occurs within spinal sensory-motor circuits remains unclear. Moreover, it is unknown what molecules are involved. Here, we demonstrate the presence of proprioceptive supernumerary synapses forming inappropriate contacts with motor neurons, resulting in miswired immature circuits. Using mouse genetics, neuronal circuit mapping, electrophysiology, and behavioral studies, we demonstrate that the inappropriate synapses are functional, leading to impaired behaviors. We further identify two complementary mechanisms responsible for their elimination: first, C3 through the classical complement pathway and second, CD47 that operates independently of classical complement signaling. This finding underlies an unexpected function for CD47 within the spinal cord, in contrast to its function in the brain. Thus, during early development, the course of elimination of inappropriately generated synapses utilizes a dual fail-safe system to ensure emergence of mature spinal motor circuits.