Pax3 induces neural circuit repair through a developmental program of directed axon outgrowth

Abstract

ABSTRACTAlthough neurotrophins can reorganise surviving neuronal connections after a lesion, clinical improvement is minimal and underlying mechanisms ill-defined, which impedes the development of effective treatment strategies. Here we show that the neurotrophin brain derived neurotrophic factor (BDNF) upregulates the transcription factor Pax3, which in turn induces axon outgrowth and synaptogenesis to repair a neural circuit. This repair depends on Pax3 increasing polysialic acid-neural cell adhesion molecule (PSA-NCAM), which is both essential for, and mediates the amount of, reinnervation. Pax3 acts pre-synaptically: its expression in reinnervating neurons induces significant axonal growth, and Pax3 knockdown abolishes reinnervation induced by BDNF, either endogenous BDNF expression during spontaneous developmental repair, or exogenous BDNF treatment in the mature nervous system. This is a novel role for Pax3. We propose that neuronal Pax3 induces PSA-NCAM expression on axon terminals to increase their motility and outgrowth, thereby promoting neural circuit reorganisation and repair.