Floor-plate-derived netrin-1 is dispensable for commissural axon guidance

Abstract

Netrin-1 is an evolutionarily conserved secreted extracellular matrix protein discovered using genetic and biochemical screens for its role in axon guidance at the central nervous system (CNS) midline1,2. Netrin-1 is expressed by cells localized at CNS midline, such as the floor plate in vertebrate embryos1,3. Growth cone turning assays and 3D gel diffusion assays showed that netrin-1 can attract commissural axons2,4–6. Loss-of-function experiments further demonstrated that commissural axon extension to the midline is severely impaired in absence of netrin-13,7–9. Together these data support a model in which commissural axons are attracted by a netrin-1 gradient diffusing from the midline. Here, we selectively ablated netrin-1 expression in floor plate cells using a Netrin-1 conditional mouse line. We found that hindbrain and spinal cord commissural axons develop normally in absence of floor plate-derived netrin-1. Furthermore, we show that netrin-1 is highly expressed by cells in the ventricular zone with the potential to release it at the pial surface where it binds to commissural axons. Importantly, netrin-1 deletion from the ventricular zone phenocopies commissural axon guidance defects previously described in Netrin-1 knockout mice. These results show that the classical textbook view that attraction of commissural axons is mediated by a gradient of floor plate-derived netrin-1 is inaccurate and that netrin-1 primarily acts locally by promoting growth cone adhesion.

Motor axons are guided to exit points in the spinal cord by Slit and Netrin signals

“…Since Netrin-1 is one of major attractive guidance cues produced both by the floor plate (Kennedy et al, 2006; Serafini et al, 1996) and by neural progenitors that constitute the ventral and lateral tissues in the neural tube (Dominici et al, 2017; Varadarajan et al, 2017), we tested if attractive Netrin-1/DCC signals are involved in guiding motor exit points to their proper position.…”

“…(Dominici et al, 2017; Hand and Kolodkin, 2017; Varadarajan et al, 2017). However, distinguishing the crucial source of Netrin-1 cue was not possible with the global Netrin-1 mutant that we used in the current study.…”

“…The major ventral attractant, Netrin-1, and its receptor DCC, guide axons and several types of neuron migration (Culotti and Merz, 1998; Kawasaki et al, 2006; Serafini et al, 1996; Yee et al, 1999). While Netrin-1 was thought to be derived primarily from the floor plate, and secreted to form a long range ventral-high gradient, recent studies provided evidence that the ventricular zone of spinal cord progenitor cells presents the crucial Netrin-1 cues to promote ventral growth of commissural axons toward the floor plate (Dominici et al, 2017; Varadarajan et al, 2017). …”

Making Dopamine Connections in Adolescence

“…The two N-terminal domains (domains VI and V) are homologues to domains in the laminin protein family, while the C-terminal domain appears unique to netrins and binds to cell surfaces and the extracellular matrix [38,39]. Netrin-1 acts as a guidance cue by influencing the “decision-making” processes of growing axons, effectively signalling whether, where and when to grow [39–42]. Netrin-1 also plays a critical role in the wiring events that follow axonal pathfinding, including target recognition, axon arborisation, and synapse formation, as well as in other processes like oligo-axonal adhesion and synaptic plasticity [38,43–45].…”

Mutations in the netrin-1 gene cause congenital mirror movements

“…Netrin-1 is expressed at the midline of the developing CNS and acts as an attractive or repulsive cue for different populations of crossing/commissural axons (2). The classical view that attraction of commissural axons is mediated by a gradient of floor-plate-derived netrin-1 has been recently challenged: netrin-1 primarily acts locally by promoting growth cone adhesion (3,4). In netrin-1-KO mice, many commissural axons fail to cross the midline in the corpus callosum, the hippocampal and anterior commissures, the corticospinal tract (CST), and the spinal cord (5-7).…”