Commissural axons in dorsal spinal cord extend axons toward netrin-1 expressing floorplate. Rig-1 represses responsiveness to Slits.

Once past the floorplate, inhibition of Robos by Rig-1 is removed, and commissural axons are repelled from the midline

After crossing, axons turn anteriorly and grow next to the floorplate, up an increasing gradient of Wnt4, a diffusible chemoattractant.

Figure 7 Axon navigation in the ventral nerve cord of Drosophila and in the vertebrate spinal cord. a, The ventral nerve cord of Drosophila. Within each segment of the Drosophila body, axons of the ventral nerve cord that project contralaterally cross the midline in either the anterior or posterior commissure. Expression of netrin and Slit by cells at the ventral midline mediates axonal navigation through the commissures. Precrossing axons are attracted by netrin-1. The insensitivity of these precrossing axons to Slit is mediated by Commissureless, a protein that sorts Robo away from the cell surface. As axons reach the midline, this repression is removed, and Robo is transported to the cell surface, rendering axons sensitive to the midline-derived Slit. Slit also controls selection of longitudinal fascicles once axons have exited the midline. b, The vertebrate spinal cord. In the developing vertebrate CNS, commissural interneurons in the dorsal regions of the spinal cord extend axons ventrally toward the netrin-1-expressing floorplate. The protein Rig-1 represses Slit responsiveness in precrossing axons. Once past the floorplate, the Slit inhibition is removed and axons are repelled from the midline. The chemoattractant Wnt4 is responsible for the anterior turn of axons which then grow next to the floorplate.

Interestingly, although precrossing commissural axons in the developing vertebrate spinal cord are not responsive to the Slit proteins, a Comm-independent mechanism seems to underlie this. Indeed, to date no Comm homologues have been identified in those vertebrate genomes sequenced. Instead, a divergent Robo homologue, Rig-1, has been shown to repress Slit responsiveness in precrossing axons (Sabatier et al., 2004). How this occurs remains unclear, but it provides an illuminating example of evolution providing two different solutions to the problem of inhibiting repulsion of precrossing commissural axons.

After the midline, axons have another decision to make, namely whether to extend anteriorly or posteriorly parallel to the midline. Recently, another protein family was found to be involved in this aspect of axon guidance, the wingless proteins (Wnts) and their Frizzled (frz) receptors. The Wnts were originally identified as morphogens, which normally induce transcriptional changes by acting inside the nucleus to pattern tissue and instructing cells to choose distinct cell fates. In contrast, axon guidance cues are defined to influence migration of motile cells or growth cones, primarily by inducing cytoskeletal changes and membrane dynamics. A surprising recent finding has been that the classical morphogens such as Wnts, Hedgehog (Hhs) and bone morphogenetic proteins (BMPs) can also act as guidance molecules in this context (reviewed in Schnorrer and Dickson, 2004). Indeed, in the rat spinal cord, a diffusible attractive gradient in the anterior-posterior direction was found to influence the guidance decision of commissural axons after crossing the midline to turn anteriorly. A search for candidates identified Wnt4. Application of Wnt function blocking SFRPs (secreted Frizzled-related proteins) resulted in stalling of axons after midline crossing. When Wnt4-expressing cell aggregates were ectopically positioned at a posterior position, these explants were able to reorient axon growth into a posterior turn. In fzd3 knockout mice, which lack the Wnt receptor, postcrossing axons exhibit random turning into anterior and posterior direction, suggesting that the signaling responsible for the anterior turn is impaired (Lyuksyutova et al., 2003). Therefore, it has become clear that the Wnt family plays an important role in axon pathfinding and can also act as guidance cues to initiate signaling pathways involved in growth cone navigation.

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