We have discovered a novel TGF-beta, UNC-129, which is largely dedicated to functioning in guiding growing neurons and migrating cells during development. TGF-betas have many known functions in development and cancer, however, UNC-129 was one of the first (and still one of the few) TGF-beta molecules that functions to regulate guidance of migrating cells and (growing) axons. We showed that this TGF-beta acts through a novel signaling mechanism not utilized by other TGF-betas for non-migration functions in development. Our major goal is to understand how the UNC-129 signaling mechanism works at a molecular level to guide migrations. We have shown that UNC-129 acts by modulating UNC-6/Netrin guidance functions. UNC-6/Netrin and its receptors represent a major cell migration guidance system first discovered by our laboratory using C. elegans and later discovered to have analogous functions in the developing vertebrate spinal cord and brain. Our recent evidence suggests that UNC-129 regulates the sensitivity of alternate receptor pathways for the UNC-6 guidance cue by interacting with UNC-5, one of the two UNC-6/Netrin receptors we discovered and characterized. Thus UNC-129 provides our first insights into the way sensitivity to gradients of morphogens and guidance cues are regulated at a molecular level. This information should prove vital to understanding how cells migrate normally, how axons migrate and grow to construct and repair the nervous system and how cancer cells become metastatic. The elucidation of these mechanisms could provide important insights into mechanisms to promote spinal cord regeneration and to prevent cancer morbidity.