UNC-129 regulates the balance between UNC-40 dependent and independent UNC-5 signaling pathways

In the worm, netrin and the TGFβ-related molecule UNC-129 form opposing dorsoventral gradients. Motor axons are repelled by netrin and attracted to UNC-129, but no TGFβ receptors appear to be involved in the attraction. This study shows that UNC-129 enhances repulsive signaling from the netrin receptor complex UNC-5/UNC-40, via a direct interaction with UNC-5. The UNC-5 receptor mediates axon repulsion from UNC-6/netrin through UNC-40 dependent (UNC-5 + UNC-40) and independent (UNC-5 alone) signaling pathways. It has been shown that UNC-40–dependent signaling is required for long-range repulsion of UNC-6/netrin; however, the mechanisms used to regulate distinct UNC-5 signaling pathways are poorly understood. We found that the C. elegans transforming growth factor β (TGF-β) family ligand UNC-129, graded opposite to UNC-6/netrin, functions independent of the canonical TGF-β receptors to regulate UNC-5 cellular responses. Our observations indicates that UNC-129 facilitates long-range repulsive guidance of UNC-6 by enhancing UNC-5 + UNC-40 signaling at the expense of UNC-5 alone signaling through interaction with the UNC-5 receptor. This increases the set point sensitivity of growth cones to UNC-6/netrin as they simultaneously migrated up the UNC-129 gradient and down the UNC-6 gradient. Similar regulatory interactions between oppositely graded extracellular cues may be a common theme in guided cell and axon migrations.