It takes a village to raise a branch: Cellular mechanisms of the initiation of axon collateral branches

Abstract

The formation of axon collateral branches from the pre-existing shafts of axons is an important aspect of neurodevelopment and the response of the nervous system to injury. This article provides an overview of the role of the cytoskeleton and signaling mechanisms in the formation of axon collateral branches. Both the actin filament and microtubule components of the cytoskeleton are required for the formation of axon branches. Recent work has begun to shed light on how these two elements of the cytoskeleton are integrated by proteins that functionally or physically link the cytoskeleton. While a number of signaling pathways have been determined as having a role in the formation of axon branches, the complexity of the downstream mechanisms and links to specific signaling pathways remain to be fully determined. The regulation of intra-axonal protein synthesis and organelle function are also emerging as components of signal-induced axon branching. Although much has been learned in the last couple of decades about the mechanistic basis of axon branching we can look forward to continue elucidating this complex biological phenomenon with the aim of understanding how multiple signaling pathways, cytoskeletal regulators and organelles are coordinated locally along the axon to give rise to a branch.

The nano-architecture of the axonal cytoskeleton

“…Unlike actin waves, the patches are nonprotrusive, focal accumula tions within the shaft. Available data support the notion that actin patches in distal axons are involved in the emergence of axonal filopodia and branches 159,160 .…”

MAP7 regulates axon morphogenesis by recruiting kinesin-1 to microtubules and modulating organelle transport

“…Neuronal cell functions, including axon morphogenesis, require proper regulation of intracellular transport on microtubules via a variety of motor and non-motor microtubule-associated proteins (MAPs) ( Armijo-Weingart and Gallo, 2017 ; Kalil and Dent, 2014 ; Kapitein and Hoogenraad, 2015 ; Kevenaar and Hoogenraad, 2015 ). Motor proteins consume ATP to move membrane or protein cargos along microtubules, whereas non-motor MAPs often modulate microtubule assembly dynamics and stability ( Kapitein and Hoogenraad, 2015 ).…”

“…Axon branching can be further divided into branch formation and branch growth. These processes involve the regulation of microtubule assembly/stability by non-motor MAPs and organelle transport by motor proteins ( Armijo-Weingart and Gallo, 2017 ; Baas et al, 2016 ; Dent et al, 2011 ; Gallo, 2011 ). For example, kinesin-1 stabilizes axonal arbors and promotes branch growth ( Seno et al, 2016 ); and non-motor MAPs, including doublecortin and MAP1B, appear to suppress branch formation ( Barnat et al, 2016 ; Bilimoria et al, 2010 ; Bouquet et al, 2004 ; Tymanskyj et al, 2012 ).…”

The role of mitochondria in axon development and regeneration

“…Mitochondria are thus best considered to have a permissive role by determining where along the axon branches can form, but ultimately, the specific site of branch formation is likely driven by the spatio‐temporal convergence of the many molecular mechanisms required to establish a branch (i.e., regulation of microtubule dynamics and stabilization, directed traffic, regulation of actin filament dynamics, etc. ; Gallo, ; Armijo‐Weingart and Gallo, ).…”