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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.

Original publication

DOI

10.1016/j.devcel.2015.11.008

Type

Journal article

Journal

Dev Cell

Publication Date

07/12/2015

Volume

35

Pages

537 - 552

Keywords

ADAM Proteins, ADAM17 Protein, Animals, Axons, CHO Cells, Cell Membrane, Cell Movement, Cricetulus, Gene Expression Regulation, Developmental, HEK293 Cells, Humans, Ligands, Membrane Proteins, Mice, Nervous System, Neurons, Phenotype, Protein Structure, Tertiary, Retina, Signal Transduction