Pum2 Shapes the Transcriptome in Developing Axons through Retention of Target mRNAs in the Cell Body

Localized protein synthesis is fundamental for neuronal development, maintenance, and function. Transcriptomes in axons and soma are distinct, but the mechanisms governing the composition of axonal transcriptomes and their developmental regulation are only partially understood. We found that the binding motif for the RNA-binding proteins Pumilio 1 and 2 (Pum1 and Pum2) is underrepresented in transcriptomes of developing axons. Introduction of Pumilio-binding elements (PBEs) into mRNAs containing a β-actin zipcode prevented axonal localization and translation. Pum2 is restricted to the soma of developing neurons, and Pum2 knockdown or blocking its binding to mRNA caused the appearance and translation of PBE-containing mRNAs in axons. Pum2-deficient neurons exhibited axonal growth and branching defects in vivo and impaired axon regeneration in vitro. These results reveal that Pum2 shapes axonal transcriptomes by preventing the transport of PBE-containing mRNAs into axons, and they identify somatic mRNAs retention as a mechanism for the temporal control of intra-axonal protein synthesis.