C3 and CD47 dependent mechanisms in the refinement of sensory-motor circuits during spinal cord development

Abstract

AbstractOverground movement in mammals require the timely and appropriate assembly of spinal sensory-motor circuits. Within spinal cord, sensory neurons, spinal interneurons and motor neurons are key players forming intricate neuronal circuits to ensure proper motor control. The formation of neuronal circuits starts at embryonic period and continues into postnatal development. During this process supernumerary synapses are pruned and refinement of immature circuits occurs, making way for emergence of mature circuits. A major aspect of the sensory-motor circuits’ refinement involves the elimination of inappropriate synapses, the molecular mechanisms of which are relatively unknown. We have investigated the molecular mechanisms involved in the elimination of inappropriate proprioceptive synapses from motor neurons by focusing on the classical complement proteins C3 and C1q, as well as the integrin associated protein CD47. Using mouse genetics, viral-mediated neuronal map strategies together with physiological, morphological and molecular biology assays, we found that inappropriate synaptic elimination occurs during early development utilizing both C3 and C1q proteins, but importantly and totally unexpectedly, the CD47 protein. Taken together, our study demonstrates that refinement of immature sensory-motor circuits in the spinal cord is mediated by classical complement dependent mechanisms as well as CD47-dependent mechanisms, uncovering a new role for CD47 as a major player in synapse elimination.