Analysis of the TGF- β Family Ligand UNC-129 as a Novel Regulator of Netrin Signaling in Caenorhabditis elegans

Abstract

UNC-129 is a TGF-β family ligand that regulates ventral to dorsal migration of commissural motor axons in C. elegans. Mutations in unc-129 result in motor axons 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-β 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. BMP7, a human BMP protein similar to UNC-129, was able to directly interact with UNC-5 and its mammalian homologue RCM. 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. To further examine the mechanism of UNC-129 function on UNC-5 signaling, I examined candidate receptors that might function with UNC-129 to regulate UNC-5. In addition, I performed a genetic screen to isolate suppressors of distal tip cell defects resulting from the ectopic expression of UNC-129 that implicates EGF receptor signaling in the ventral to dorsal migration of Distal Tip Cells. Further analysis of these components of UNC-129 signaling will contribute to our understanding of UNC-129 function and regulation and broaden our understanding of how axonal migration is controlled over long distances.