UNC-129 is a TGF-beta family ligand that regulates ventral to dorsal migration of commissural motor axons in C. elegans. Mutations in
unc-129 result in motoraxons that do not accomplish normal ventral to dorsal migration, but instead deviate from their proper course. Genetic evidence demonstrates that UNC-129 does not function as other TGF-beta family ligands, through the classical type I and type II serine/threonine kinase receptors, but instead regulates axon guidance through a novel signaling pathway. Genetic interactions between null alleles of
unc-129 and
unc-5,
unc-40 and
unc-6 revealed that
unc-129 acts within the UNC-5 signaling pathway to regulate axon guidance, cell migration and patterning of the male tail. Analysis of
unc-40 and
unc-129 compound null mutants demonstrates that UNC-129 acts specifically to promote UNC-5+UNC-40 signaling. In contrast, overexpression studies using ectopically expressed UNC-129 suggest that UNC-129 acts to inhibit UNC-40 independent UNC-5 signaling. Together, these data suggest a model where UNC-129 regulates the decision between UNC-40 dependent and independent UNC-5 signaling. The result of this, for cells and axons migrating along the ventral-dorsal axis, is to increase the sensitivity of cells and axons to decreasing levels of UNC-6/Netrin by switching from UNC-5 signaling to UNC-5+UNC-40 signaling.