Rnf165/Ark2C enhances BMP-Smad signaling to mediate motor axon extension.

Peter Scheiffele,Claire E Kelly,Jonathan Godwin,Efstathia Thymiakou,Shinya Tanaka,James E Dixon,Vasso Episkopou

doi:10.1371/journal.pbio.1001538

Abstract

Author SummaryMotor neurons control movement via long axons that extend from the spinal cord to muscles as far as in distant limbs. Little is known about factors that regulate this extensive axonal growth in the periphery. Here we report that the ubiquitin ligase Ark2C (Arkadia2) is expressed in neurons and can serve to amplify neuronal responses to specific signals. We find that these signals belong to the Bone Morphogenetic Protein (BMP) family of secreted factors, which are highly expressed in the periphery and known to regulate the development of the limbs. Loss of Ark2C gene function in mice results in inefficient growth of motor axons to distant muscles, and we show that this process is regulated by BMP signaling. Ark2C targets BMP inhibitors for destruction, and therefore the presence of Ark2C helps to enhance BMP signaling, which in turn is necessary for the innervation of distal muscles. Our experiments reveal a previously unknown function of BMP in motor axon growth and describe a molecular mechanism for how axons and limbs coordinate their growth.

Highlights

The assembly of neural circuits is complex and highly specific
We report that the ubiquitin ligase Ark2C (Arkadia2) is expressed in neurons and can serve to amplify neuronal responses to specific signals. We find that these signals belong to the Bone Morphogenetic Protein (BMP) family of secreted factors, which are highly expressed in the periphery and known to regulate the development of the limbs
Motor axons are amongst the longest in the body and both intrinsic and extrinsic factors have been shown to play a role in their elongation

Summary

Introduction

The assembly of neural circuits is complex and highly specific. Progenitors and early postmitotic neurons acquire an intrinsic genetic program that controls circuit assembly steps including axonal path finding and synaptic partner recognition [1,2,3]. Extrinsic signals that control axon initiation and advancement are beginning to be identified [4,5]. Motor axons follow precise paths through peripheral tissues [6], and extrinsic signals acting directly upon the motor axons [7] or upon adjacent sensory axons [8] have been implicated in steering their advancement. Intrinsic properties of different MN subtypes produce varying responses to extrinsic signals creating a highly specific pattern of innervation [9]. The developing peripheral tissue expresses many cytokines for its own development and the role of many of these in the manipulation of motor axon growth has not been fully addressed

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