Trans-Axonal Signaling in Neural Circuit Wiring

Abstract

The development of neural circuits is a complex process that relies on the proper navigation of axons through their environment to their appropriate targets. While axon–environment and axon–target interactions have long been known as essential for circuit formation, communication between axons themselves has only more recently emerged as another crucial mechanism. Trans-axonal signaling governs many axonal behaviors, including fasciculation for proper guidance to targets, defasciculation for pathfinding at important choice points, repulsion along and within tracts for pre-target sorting and target selection, repulsion at the target for precise synaptic connectivity, and potentially selective degeneration for circuit refinement. This review outlines the recent advances in identifying the molecular mechanisms of trans-axonal signaling and discusses the role of axon–axon interactions during the different steps of neural circuit formation.

An estimation of the absolute number of axons indicates that human cortical areas are sparsely connected

“…Indeed, we estimate that approximately 96% of the WM is composed of interareal axons. What these observations suggest is that the major tracts arise from the tendency of axons to grow in alignment with axons that are already present using established mechanisms of adhesion and fasciculation [39]. Thus, axons are free to join tracts at various points, and tend to proceed together (fasciculate), but again are free to leave whenever they approach their own target.…”

An estimation of the absolute number of axons indicates that human cortical areas are sparsely connected

“…Indeed, we estimate that ~96% of the white matter is composed of inter-areal axons. What these observations suggest is that the major tracts arise from the tendency of axons to grow in alignment with axons which are already present using established mechanisms of adhesion and fasciculation [38]. Thus axons are free to join tracts at various points, and tend to proceed together (fasciculate), but again are free to leave whenever they approach their own target.…”

Molecular topography of an entire nervous system

“…For this analysis, we utilized the nerve ring ( Figure 9A), the largest expanse of neuropil in the C. elegans nervous system, because electron microscope reconstructions from multiple animals have detailed both membrane contacts and synapses in this region (Brittin et al, 2020;Cook et al, 2019;White et al, 1986;Witvliet et al, 2020). We limited our analyses to putative cell adhesion molecules (CAMs), many of which have documented roles in axon pathfinding, selective axon fasciculation and synapse formation within nervous systems (Bruce et al, 2017;Colón-Ramos et al, 2007;Kim and Emmons, 2017;Sanes and Zipursky, 2020;Shen and Bargmann, 2003;Siegenthaler et al, 2015;Spead and Poulain, 2020;Sperry, 1963;Wang et al, 2011). 141 CAMs were detected in neurons in our single cell RNA-Seq dataset (list of CAMs compiled from (Cox et al, 2004;Hobert, 2013), see Table S7).…”