Key proteins and molecular pathways during nervous system development often emerge later in life as important mediators of neurodegenerative disease. One such example is the ephrin receptor EphA4, which provides guidance signals to help developing axons reach their final cellular targets, and was recently identified as a modifier gene in ALS (see Aug 2012 news story). New findings published 20 October 2014 in Current Biology shed light on the role of proteolysis in regulating Eph-ephrin signaling during development, and reveal potential new avenues for modifying ALS progression. Researchers from the Max Planck Institute of Neurobiology in Martinsried and the Institut de Recherches Cliniques de Montréal demonstrate that proteolytic cleavage of Eph receptors is necessary to ‘unmask’ ephrins on the cellular targets, and thereby provide the necessary navigational signals to axons through axonally-expressed Eph receptors. Where do developing motor axons go when EphA4 proteolytic cleavage is blocked? Click here to find out.