Cofilin regulates axon growth and branching of Drosophila γ-neurons.

Sriram Sudarsanam,Shiri Yaniv,Hagar Meltzer,Oren Schuldiner

doi:10.1242/jcs.232595

Abstract

ABSTRACTThe mechanisms that control intrinsic axon growth potential, and thus axon regeneration following injury, are not well understood. Developmental axon regrowth of Drosophila mushroom body γ-neurons during neuronal remodeling offers a unique opportunity to study the molecular mechanisms controlling intrinsic growth potential. Motivated by the recently uncovered developmental expression atlas of γ-neurons, we here focus on the role of the actin-severing protein cofilin during axon regrowth. We show that Twinstar (Tsr), the fly cofilin, is a crucial regulator of both axon growth and branching during developmental remodeling of γ-neurons. tsr mutant axons demonstrate growth defects both in vivo and in vitro, and also exhibit actin-rich filopodial-like structures at failed branch points in vivo. Our data is inconsistent with Tsr being important for increasing G-actin availability. Furthermore, analysis of microtubule localization suggests that Tsr is required for microtubule infiltration into the axon tips and branch points. Taken together, we show that Tsr promotes axon growth and branching, likely by clearing F-actin to facilitate protrusion of microtubules.

Highlights

The limited regeneration of injured adult neurons within central nervous systems is due to a combination of inhibitory environments (Tedeschi and Bradke, 2017) and reduced intrinsic growth ability (Mahar and Cavalli, 2018)
While we have previously shown that axon regrowth is a genetically controlled program, dependent upon the nuclear receptor transcription factors Unfulfilled (UNF, known as Hr51; Yaniv et al, 2012) and Ecdysone-induced protein 75B (Eip75B; Rabinovich et al, 2016), the molecular machinery that governs growth in this context is largely unknown
Tsr is required for axon growth of mushroom body (MB) γ-neurons We have recently uncovered the expression profiles of developing MB γ-neurons at a fine temporal resolution (Alyagor et al, 2018)

Summary

Introduction

The limited regeneration of injured adult neurons within central nervous systems is due to a combination of inhibitory environments (Tedeschi and Bradke, 2017) and reduced intrinsic growth ability (Mahar and Cavalli, 2018). Intrinsic growth abilities decrease with age, concomitant with lower regeneration capacity (Wang et al, 2007). Uncovering the factors that determine intrinsic growth potential in young developing neurons, holds the promise of furthering our understanding regarding factors that normally restrict regeneration. Neuronal remodeling is a conserved mechanism, which includes the elimination of axons and synaptic connections, often followed by formation of new connections to sculpt mature neural networks (Luo and O’Leary, 2005; Yaron and Schuldiner, 2016). Remodeling of the Drosophila mushroom body (MB), a center for olfactory

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