Figure 2.

Shh and Wnts guide commissural axons in the vertebrate spinal cord. (A) Pre-crossing commissural axons (blue) are attracted ventrally toward the midline by an increasing gradient of Shh produced in the floorplate (green). The attractive effect of Shh is mediated by Smoothened (Smo) and Brother of CDO (Boc) in a transcription-independent manner. Instead, the activation of Src family kinases (SFK) induces cytoskeletal rearrangements in the growth cone. (B) The response of commissural axons to Shh switches from attraction to repulsion when axons reach the midline. Post-crossing commissural axons are pushed anteriorly by a posterior^high to anterior^low gradient of Shh (red). The repellent activity of Shh is mediated by Hedgehog-interacting protein (Hhip), a receptor that is transiently upregulated on commissural axons at the time of their turning into the longitudinal axis. An additional signaling co-receptor may also be involved. (C) An anterior^high to posterior^low gradient of Wnt activity works in parallel to Shh repulsion to attract post-crossing commissural axons anteriorly. Depending on the species, Wnt4, Wnt5a, and Wnt7a are attractants for post-crossing commissural axons via non-canonical pathways. In mouse, Fz3, in response to Wnt4/Wnt7b, activates a complex containing an atypical protein kinase C (aPKCζ). In response to Wnt5a, the PCP pathway is activated. See text for more details. (D) In chick, Shh was shown to shape Wnt activity indirectly. Wnt5a and Wnt7a are expressed uniformly along the longitudinal axis. In addition to its direct effect on post-crossing commissural axons, Shh induces the expression of the Wnt antagonist Sfrp1 in a posterior^high to anterior^low gradient in the floorplate. The antagonistic activity of Sfrp in turn regulates the activity of Wnts in the floorplate, such that an attractive “activity gradient” of Wnt is formed. Thus, Shh (red) and Wnt (green) gradients collaborate to guide post-crossing commissural axons anteriorly.