Commissural axon guidance in the developing spinal cord: from Cajal to the present day

Abstract

During neuronal development, the formation of neural circuits requires developing axons to traverse a diverse cellular and molecular environment to establish synaptic contacts with the appropriate postsynaptic partners. Essential to this process is the ability of developing axons to navigate guidance molecules presented by specialized populations of cells. These cells partition the distance traveled by growing axons into shorter intervals by serving as intermediate targets, orchestrating the arrival and departure of axons by providing attractive and repulsive guidance cues. The floor plate in the central nervous system (CNS) is a critical intermediate target during neuronal development, required for the extension of commissural axons across the ventral midline. In this review, we begin by giving a historical overview of the ventral commissure and the evolutionary purpose of decussation. We then review the axon guidance studies that have revealed a diverse assortment of midline guidance cues, as well as genetic and molecular regulatory mechanisms required for coordinating the commissural axon response to these cues. Finally, we examine the contribution of dysfunctional axon guidance to neurological diseases.

Keywords: Commissural axons; Decussation; Floor plate; Midline guidance cues; Neurological diseases; Ventral commissure.

Fig. 1

Mechanisms of axon guidance. Growth cones, the motile tip of a growing axon, integrate four major categories of guidance information [3]. a, b Long range chemoattractants (a) or chemorepellents (b) that act at a distance to orient the growth cone either towards or away from the signal. c, d Contact mediated chemoattractants (c) or chemorepellents (d) that orient axons through direct contact with the growth cone

Fig. 2

Comparison of netrin1 axon guidance models. a In the chemotaxis model, netrin1 acts as a long-range guidance signal. Commissural axons grow towards a diffusible source of netrin1 protein (green) emanating from the floor plate (FP). b In the haptotaxis model, netrin1 acts as a short-range guidance cue. Neural progenitor cells (NPCs) in the ventricular zone (VZ) express netrin1 transcript (red). Netrin1 protein (green) is trafficked to the pial surface along the radial processes of the NPCs to form a growth substrate. Commissural axons extend along this netrin1 substrate, themselves accumulating netrin1 as they grow around the VZ towards the FP. Figure adapted from [13]

Fig. 3

Summary of ventral midline crossing. a In the vertebrate spinal cord, dorsal commissural neurons extend their axons ventrally. They are guided first by the roof plate (RP)-chemorepellent, mediated by the Bmps acting through BmprIb, that directs them away from the dorsal midline. Commissural axons are then directed towards the floor plate at the ventral midline, considered a classic example of an axon guidance guidepost, by action of two attractants, netrin1 and Shh, in a Dcc- and Smo/Boc-dependent mechanism, respectively. b Midline crossing is mediated by the slit/Robo pathway. The floor plate (FP) expresses the slit repellent, which is detected by the robo receptor family. Pre-crossing commissural axons are unresponsive to slit, as a consequence of the expression of Robo3, which interferes with Robo1 function. However, after crossing the midline, Robo3 expression is downregulated, such that Robo1⁺ commissural axons become sensitive to the presence of slit, guiding the axons away from the midline and preventing the axons from re-crossing the midline. c Guidance decisions are largely conserved in the Drosophila nerve cord. Attraction of commissural axons to Netrin1 is mediated by the Dcc homologue Frazzled (Fra). Similarly, Slit proteins regulate behavior of pre and post-midline crossing Robo⁺ axons through repulsive signaling. However, in Drosophila, Robo levels are regulated by Comm, which endocytoses Robo in axons, making them unable to detect slit repulsion, and thereby permits axons to cross the midline