Regulation ofnetrin-1aExpression by Hedgehog Proteins

Netrins, a family of growth cone guidance molecules, are expressed both in the ventral neural tube and in subsets of mesodermal cells. In an effort to better understand the regulation of netrins, we examined the expression of netrin-1a in mutant cyclops, no tail, and floating head zebrafish embryos, in which axial midline structures are perturbed. Netrin-1a expression requires signals present in notochord and floor plate cells. In the myotome, but not the neural tube, netrin-1a expression requires sonic hedgehog. In embryos lacking sonic hedgehog, the sonic-you locus, netrin-1a expression is reduced or absent in the myotomes but present in the neural tube. Embryos lacking sonic hedgehog express tiggy-winkle hedgehog in the floor plate, suggesting that, in the neural tube, tiggy-winkle hedgehog can compensate for the lack of sonic hedgehog in inducing netrin-1a expression. Ectopic expression of sonic hedgehog, tiggy-winkle hedgehog, or echidna hedgehog induces ectopic netrin-1a expression in the neural tube, and ectopic expression of sonic hedgehog or tiggy-winkle hedgehog, but not echidna hedgehog, induces ectopic netrin-1a expression in somites. These data demonstrate that in vertebrates netrin expression is regulated by Hedgehog signaling.