Retrograde Ret signaling controls sensory pioneer axon outgrowth.

Adam Tuttle,Catherine M Drerup,Hillary McGraw,Molly Marra,Alex V Nechiporuk

doi:10.7554/elife.46092

Abstract

The trafficking mechanisms and transcriptional targets downstream of long-range neurotrophic factor ligand/receptor signaling that promote axon growth are incompletely understood. Zebrafish carrying a null mutation in a neurotrophic factor receptor, Ret, displayed defects in peripheral sensory axon growth cone morphology and dynamics. Ret receptor was highly enriched in sensory pioneer neurons and Ret51 isoform was required for pioneer axon outgrowth. Loss-of-function of a cargo adaptor, Jip3, partially phenocopied Ret axonal defects, led to accumulation of activated Ret in pioneer growth cones, and reduced retrograde Ret51 transport. Jip3 and Ret51 were also retrogradely co-transported, ultimately suggesting Jip3 is a retrograde adapter of active Ret51. Finally, loss of Ret reduced transcription and growth cone localization of Myosin-X, an initiator of filopodial formation. These results show a specific role for Ret51 in pioneer axon growth, and suggest a critical role for long-range retrograde Ret signaling in regulating growth cone dynamics through downstream transcriptional changes.

Highlights

One major regulator of axon outgrowth and pathfinding is signaling through neurotrophic factors
Previous studies showed that ret is expressed in the posterior lateral line ganglion (pLLG) neurons and the REarranged during Transfection’ (Ret) ligand Glial cell line-Derived Neurotrophic Factor (GDNF), which is expressed by the pLL primordium (pLLP), is required for pLLG axon extension but not pLLG neuronal survival (Schuster et al, 2010)
Our work finds that the Ret51 isoform is required for sensory pioneer axon outgrowth

Summary

Introduction

One major regulator of axon outgrowth and pathfinding is signaling through neurotrophic factors. Pioneer neurons are important in the developing CNS and PNS for the initial navigation to appropriate targets, proper follower axon pathfinding, and promoting follower axon outgrowth Despite their unique role in neurodevelopment, the molecular program regulates their behavior is not well known. The pLL primordium expresses GDNF and this ligand production is required for proper pLLG axon outgrowth, but not pLLG neuron specification or survival (Schuster et al, 2010) This allowed us to explore the specific mechanisms of long-range Ret-mediated axon outgrowth in sensory pioneer neurons. This work describes a novel requirement for Ret in axon growth and pioneer neuron development, identifies a novel regulator of phosphorylated Ret retrograde transport, and suggests long-range retrograde Ret signaling regulates downstream transcriptional targets which are required for pioneer sensory axon growth cone dynamics

Results

Discussion

Materials and methods