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

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. A requirement for UNC-40 dependent signaling has been shown in long-range repulsion from UNC-6/netrin, however, the mechanisms used to regulate distinct UNC-5 signaling pathways are poorly understood. Here we demonstrate that the C. elegans 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. We provide evidence 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 migrate 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.