Netrin-1 acts as a repulsive guidance cue for sensory axonal projections toward the spinal cord.
During early development, the ventral spinal cord expresses chemorepulsive signals that act on dorsal root ganglion (DRG) axons to help orient them toward the dorsolateral part of the spinal cord. However, the molecular nature of this chemorepulsion is mostly unknown. We report here that netrin-1 acts as an early ventral spinal cord-derived chemorepellent for DRG axons. In the developing mouse spinal cord, netrin-1 is expressed in the floor plate of the spinal cord, and the netrin receptor Unc5c is expressed in DRG neurons. We show that human embryonic kidney cell aggregates secreting netrin-1 repel DRG axons and that netrin-1-deficient ventral spinal cord explants lose their repulsive influence on DRG axons. In embryonic day 10 netrin-1 mutant mice, we find that DRG axons exhibit transient misorientation. Furthermore, by means of gain-of-function analyses, we show that ectopic netrin-1 in the dorsal and intermediate spinal cord prevents DRG axons from being directed toward the dorsal spinal cord. Together, these findings suggest that netrin-1 contributes to the formation of the initial trajectories of developing DRG axons as a repulsive guidance cue.
Department of Anatomy, Fukushima Medical University School of Medicine, Fukushima City, Fukushima 960-1295, Japan. tmasu@fmu.ac.jp
Tomoyuki
T
Masuda
Keisuke
K
Watanabe
Chie
C
Sakuma
Kazuhiro
K
Ikenaka
Katsuhiko
K
Ono
Hiroyuki
H
Yaginuma
D000818:Animals; D001369:Axons / Q000502:physiology*; D002460:Cell Line; D002633:Chemotaxis / Q000502:physiology*; D003463:Cues; D004622:Embryo, Mammalian / Q000378:metabolism / Q000502:physiology; D047108:Embryonic Development; D005727:Ganglia, Spinal / Q000166:cytology / Q000196:embryology*; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D008817:Mice, Mutant Strains; D009154:Mutation; D009414:Nerve Growth Factors / Q000235:genetics / Q000502:physiology*; D000075386:Netrin Receptors; D000075388:Netrin-1; D009434:Neural Pathways / Q000502:physiology; D009475:Neurons, Afferent / Q000502:physiology*; D017475:Receptors, Nerve Growth Factor / Q000378:metabolism; D013116:Spinal Cord / Q000196:embryology*; D009435:Synaptic Transmission / Q000502:physiology*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000502:physiology*
C000617351:NTN1 protein, human; D009414:Nerve Growth Factors; D000075386:Netrin Receptors; C000617353:Ntn1 protein, mouse; D017475:Receptors, Nerve Growth Factor; D025521:Tumor Suppressor Proteins; C105653:Unc5c protein, mouse; D000075388:Netrin-1