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The Journal of Neuroscience, October 8, 2008, 28(41):10380-10385; doi:10.1523/JNEUROSCI.1926-08.2008

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Brief Communications
Netrin-1 Acts as a Repulsive Guidance Cue for Sensory Axonal Projections toward the Spinal Cord

Tomoyuki Masuda,^1 * Keisuke Watanabe,^2,3 * Chie Sakuma,^1 * Kazuhiro Ikenaka,³ Katsuhiko Ono,³ and Hiroyuki Yaginuma¹

¹Department of Anatomy, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan, ²Department of Morphological Neural Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan, and ³Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki 444-8787, Japan

Correspondence should be addressed to Dr. Tomoyuki Masuda, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan. Email: tmasu{at}fmu.ac.jp

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.

Key words: spinal cord; dorsal root ganglion; chemorepulsion; netrin-1; axonal guidance; Unc5; floor plate

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Received Dec. 5, 2007; revised July 14, 2008; accepted Sept. 9, 2008.

Correspondence should be addressed to Dr. Tomoyuki Masuda, Fukushima Medical University School of Medicine, 1 Hikarigaoka, Fukushima City, Fukushima 960-1295, Japan. Email: tmasu{at}fmu.ac.jp

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