The Fragile X Messenger Ribonucleoprotein 1 Participates in Axon Guidance Mediated by the Wnt/Planar Cell Polarity Pathway

Abstract

The Planar cell polarity (PCP) pathway is known to mediate the function of the Wnt proteins in growth cone guidance. Here, we show that the PCP pathway may directly influence local protein synthesis within the growth cones. We found that Fragile X Messenger Ribonucleoprotein 1 (FMRP) interacts with Fzd3. This interaction is negatively regulated by Wnt5a, which induces FMRP phosphorylation. Knocking down FMRP via electroporating shRNAs into the dorsal spinal cord lead to a randomization of anterior-posterior turning of post-crossing commissural axons, which could be rescued by a FMRP rescue construct. Using RNAscope, we found that some of the FMRP target mRNAs encoding PCP components, PRICKLE2 and Celsr2, as well as regulators of cytoskeletal dynamics and components of cytoskeleton, APC, Cfl1, Map1b, Tubb3 and Actb, are present in the commissural neuron growth cones. Our results suggest that PCP signaling may regulate growth cone guidance, at least in part, by regulating local protein synthesis in the growth cones through via an interaction between Frizzled3 and FMRP.