Fig. 2.

Models for the long- and short-range activities of netrin1. (A) In the long-range gradient model, the RP-derived Bmps act as a chemorepellent “pushing” commissural axons away from the dorsal midline, while FP-derived netrin1 and Shh function as chemoattractants “pulling” commissural axons to the ventral midline. (B) In the short-range model, pial-netrin1 first orients early born commissural axons to extend ventrally. NPCs transcribe netrin1 (red) and then deposit netrin1 protein (green) on the pial surface, where it may act as a growth substrate to promote axon extension (Varadarajan et al., 2017). (C) As development progresses, pre-crossing commissural axons extend into the ventral spinal cord, and no longer grow adjacent to pial-netrin1 (dotted green line). Rather, they project precisely around a “hederal” boundary of netrin1 expressing NPCs (orange line). We have proposed that the netrin1 hederal boundary promotes directed axon fasciculation while preventing innervation of netrin1 expressing cells. This activity permits commissural axons to grow around the VZ. (D) Commissural axons extend across the FP in a highly fasciculated bundle within a narrow corridor bounded by hederal-netrin1 and pial-netrin1. Post-crossing commissural axons then turn rostrally to extend in the ventral funiculus, again growing adjacent to a pial-netrin1 substrate (solid green line). Concomitantly, a domain of netrin1 expressing cells (red) emerges adjacent to the DREZ, which continue to sculpt axonal trajectories within the spinal cord. (E–G) We propose that the netrin1 produced by neural progenitors is transported to the pial surface in their progenitor endfeet, and then transfers from this pial-substrate to Dcc⁺ commissural axons (E) (Varadarajan et al., 2017; Varadarajan & Butler, 2017). Dcc and netrin1 then interact in cis to promote the selective fasciculation and growth commissural axons around netrin1 expressing NPCs (F). In absence of Dcc, netrin1 does accumulate on the pial surface, but does not transfer to commissural axons. These axons fail to fasciculate and grow randomly, including into the VZ (G).