LRRTM4 controls cell migration via Glypican interactions

Summary Leucine-rich-repeat-transmembrane neuronal proteins (LRRTMs) play a major role in neuronal connectivity and synapse formation, but their function during early development remains largely unexplored and roles in cell migration have not been described. Here, we identify LRRTM4 as a major coordinator of cell migration within the developing cortex and in cancer cells. Using structural predictions and site-directed mutagenesis to abolish the LRRTM4-glypican interaction, we show that LRRTMs interact with the core domain of glypicans, which, in the midgestational murine cortex, are presented by radial glia cells. We demonstrate that glypican-bound LRRTM4 mediates contact-repulsion in migrating neurons and cancer cells in vitro . Our results demonstrate that LRRTMs are used by migrating cells responding to glypicans, and that this signaling system is active in migrating cancer cells and during development.