Saijilafu^1,*, Eun-Mi Hur^1,2,*, Chang-Mei Liu¹, Zhongxian Jiao¹, Wen-Lin Xu¹ & Feng-Quan Zhou^1,3

¹ Department of Orthopaedic Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ² Center for Neuroscience, Brain Science Institute, Korea Institute of Science and Technology, Seoul 136-791, Republic of Korea. ³ The Solomon H. Snyder Department of Neuroscience, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA. ^* These authors contributed equally to this work.

Corresponding author:Feng-Quan Zhou

Abstract
In contrast to neurons in the central nervous system, mature neurons in the mammalian peripheral nervous system (PNS) can regenerate axons after injury, in part, by enhancing intrinsic growth competence. However, the signalling pathways that enhance the growth potential and induce spontaneous axon regeneration remain poorly understood. Here we reveal that phosphatidylinositol 3-kinase (PI3K) signalling is activated in response to peripheral axotomy and that PI3K pathway is required for sensory axon regeneration. Moreover, we show that glycogen synthase kinase 3 (GSK3), rather than mammalian target of rapamycin, mediates PI3K-dependent augmentation of the growth potential in the PNS. Furthermore, we show that PI3K-GSK3 signal is conveyed by the induction of a transcription factor Smad1 and that acute depletion of Smad1 in adult mice prevents axon regeneration in vivo. Together, these results suggest PI3K-GSK3 Smad1 signalling as a central module for promoting sensory axon regeneration in the mammalian nervous system.