Sonic hedgehog guides post-crossing commissural axons both directly and indirectly by regulating Wnt activity

After midline crossing, axons of dorsolateral commissural neurons turn rostrally into the longitudinal axis of the spinal cord. In mouse, the graded distribution of Wnt4 attracts post-crossing axons rostrally. In contrast, in the chicken embryo, the graded distribution of Sonic hedgehog (Shh) guides post-crossing axons by a repulsive mechanism mediated by hedgehog-interacting protein. Based on these observations, we tested for a possible cooperation between the two types of morphogens. Indeed, we found that Wnts also act as axon guidance cues in the chicken spinal cord. However, in contrast to the mouse, Wnt transcription did not differ along the anteroposterior axis of the spinal cord. Rather, Wnt function was regulated by a gradient of the Wnt antagonist Sfrp1 (Secreted frizzled-related protein 1) that in turn was shaped by the Shh gradient. Thus, Shh affects post-crossing axon guidance both directly and indirectly by regulating Wnt function.