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First published online 1 March 2006
doi: 10.1242/dev.02312

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Dorsally derived netrin 1 provides an inhibitory cue and elaborates the `waiting period' for primary sensory axons in the developing spinal cord

¹ Department of Physiological Sciences, School of Life Science, The Graduate University for Advanced Studies (Sokendai), 5-1 Higashiyama, Myodaiji, Okazaki 444-8787, Japan.
² Division of Neurobiology and Bioinformatics, National Institute for Physiological Sciences, Okazaki 444-8787, Japan.
³ Department of Morphological Neural Science, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan.
⁴ Department of Morphological Brain Science, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan.
⁵ Howard Hughes Medical Institute and The Jackson Laboratory, Bar Harbor, MN 04609, USA.

^* Author for correspondence (e-mail: katsono{at}nips.ac.jp)

Accepted 3 February 2006

Dorsal root ganglion (DRG) neurons extend axons to specific targets in the gray matter of the spinal cord. During development, DRG axons grow into the dorsolateral margin of the spinal cord and projection into the dorsal mantle layer occurs after a `waiting period' of a few days. Netrin 1 is a long-range diffusible factor expressed in the ventral midline of the developing neural tube, and has chemoattractive and chemorepulsive effects on growing axons. Netrin 1 is also expressed in the dorsal spinal cord. However, the roles of dorsally derived netrin 1 remain totally unknown. Here, we show that dorsal netrin 1 controls the correct guidance of primary sensory axons. During the waiting period, netrin 1 is transiently expressed or upregulated in the dorsal spinal cord, and the absence of netrin 1 results in the aberrant projection of sensory axons, including both cutaneous and proprioceptive afferents, into the dorsal mantle layer. Netrin 1 derived from the dorsal spinal cord, but not the floor plate, is involved in the correct projection of DRG axons. Furthermore, netrin 1 suppresses axon outgrowth from DRG in vitro. Unc5c^rcm mutant shows abnormal invasion of DRG axons as observed in netrin 1 mutants. These results are the first direct evidence that netrin 1 in the dorsal spinal cord acts as an inhibitory cue for primary sensory axons and is a crucial signal for the formation of sensory afferent neural networks.

Key words: Network formation, Dcc, Unc5c, RCM, Dorsal funiculus, DRG, Mouse

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