title: ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A.
abstract: During embryonic development, axons can gain and lose sensitivity to guidance cues, and this flexibility is essential for the correct wiring of the nervous system. Yet, the underlying molecular mechanisms are largely unknown. Here we show that receptor cleavage by ADAM (A Disintegrin And Metalloprotease) metalloproteases promotes murine sensory axons loss of responsiveness to the chemorepellant Sema3A. Genetic ablation of ADAM10 and ADAM17 disrupts the developmental downregulation of Neuropilin-1 (Nrp1), the receptor for Sema3A, in sensory axons. Moreover, this is correlated with gain of repulsive response to Sema3A. Overexpression of Nrp1 in neurons reverses axonal desensitization to Sema3A, but this is hampered in a mutant Nrp1 with high susceptibility to cleavage. Lastly, we detect guidance errors of proprioceptive axons in ADAM knockouts that are consistent with enhanced response to Sema3A. Our results provide the first evidence for involvement of ADAMs in regulating developmental switch in responsiveness to axonal guidance cues.
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Erez
authors.initials: E
authors.lastname: Romi
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Irena
authors.initials: I
authors.lastname: Gokhman
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Eitan
authors.initials: E
authors.lastname: Wong
authors.affiliation: Department of Plant sciences, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Niv
authors.initials: N
authors.lastname: Antonovsky
authors.affiliation: Institute for Pharmacology and Toxicology, RWTH Aachen University, Aachen 52062, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Ludwig
authors.affiliation: Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Irit
authors.initials: I
authors.lastname: Sagi
authors.affiliation: Institut fur Biochemie, Christian-Albrechts-Universität, Kiel D-24098, Germany.
authors.forename: Paul
authors.initials: P
authors.lastname: Saftig
authors.affiliation: Laboratory of Brain Development and Repair, Rockefeller University, New York, New York 10065, USA.
authors.forename: Marc
authors.initials: M
authors.lastname: Tessier-Lavigne
authors.affiliation: Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Avraham
authors.initials: A
authors.lastname: Yaron
mesh_terms: D051722:ADAM Proteins / Q000235:genetics*; D000072197:ADAM10 Protein; D000072198:ADAM17 Protein; D053829:Amyloid Precursor Protein Secretases / Q000235:genetics; D000818:Animals; D001369:Axons / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D008565:Membrane Proteins / Q000235:genetics; D051379:Mice; D039942:Neuropilin-1 / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D040121:Semaphorin-3A / Q000378:metabolism*; D011984:Sensory Receptor Cells / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; C488217:Sema3a protein, mouse; C488218:Sema3a protein, rat; D040121:Semaphorin-3A; D039942:Neuropilin-1; D053829:Amyloid Precursor Protein Secretases; D051722:ADAM Proteins; D000072197:ADAM10 Protein; C542371:ADAM10 protein, rat; C491234:Adam10 protein, mouse; D000072198:ADAM17 Protein; C000606463:Adam17 protein, mouse; C000606464:Adam17 protein, rat