Lrig2 Negatively Regulates Ectodomain Shedding of Axon Guidance Receptors by ADAM Proteases

• Published in: Developmental cell 2015-12, Vol.35 (5), p.537-552
• Main Authors: van Erp, Susan, van den Heuvel, Dianne M.A., Fujita, Yuki, Robinson, Ross A., Hellemons, Anita J.C.G.M., Adolfs, Youri, Van Battum, Eljo Y., Blokhuis, Anna M., Kuijpers, Marijn, Demmers, Jeroen A.A., Hedman, Håkan, Hoogenraad, Casper C., Siebold, Christian, Yamashita, Toshihide, Pasterkamp, R. Jeroen
• Format: Article
• Language: English
• Subjects: ADAM Proteins - metabolism; ADAM17 Protein; Animals; Axons - metabolism; Cell Membrane - metabolism; Cell Movement; CHO Cells; Cricetulus; Gene Expression Regulation, Developmental; HEK293 Cells; Humans; Ligands; Membrane Glycoproteins; Membrane Proteins - metabolism; Mice; Nervous System - embryology; Neurons - metabolism; Phenotype; Protein Structure, Tertiary; Retina - embryology; Signal Transduction
• ISSN: 1534-5807; 1878-1551; 1878-1551
• DOI: 10.1016/j.devcel.2015.11.008

Many guidance receptors are proteolytically cleaved by membrane-associated metalloproteases of the ADAM family, leading to the shedding of their ectodomains. Ectodomain shedding is crucial for receptor signaling and function, but how this process is controlled in neurons remains poorly understood. Here, we show that the transmembrane protein Lrig2 negatively regulates ADAM-mediated guidance receptor proteolysis in neurons. Lrig2 binds Neogenin, a receptor for repulsive guidance molecules (RGMs), and prevents premature Neogenin shedding by ADAM17 (TACE). RGMa reduces Lrig2-Neogenin interactions, providing ADAM17 access to Neogenin and allowing this protease to induce ectodomain shedding. Regulation of ADAM17-mediated Neogenin cleavage by Lrig2 is required for neurite growth inhibition by RGMa in vitro and for cortical neuron migration in vivo. Furthermore, knockdown of Lrig2 significantly improves CNS axon regeneration. Together, our data identify a unique ligand-gated mechanism to control receptor shedding by ADAMs and reveal functions for Lrigs in neuron migration and regenerative failure. [Display omitted] •Lrig2 negatively regulates ectodomain shedding of Neogenin by ADAM17•RGMa inhibits Lrig2-Neogenin binding, allowing ADAM17-mediated cleavage of Neogenin•Lrig2 controls neuron migration, and Lrig2 knockdown improves axon regeneration•Lrig2 inhibits ectodomain shedding of multiple, distinct ADAM17 substrates How proteolytic cleavage of cell-surface proteins is controlled in neurons is incompletely understood. Van Erp and van den Heuvel et al. show that Lrig2 negatively regulates ADAM17-mediated ectodomain shedding of the guidance receptor Neogenin. This process is required for proper neuron migration during embryonic development and during axon regeneration.