ADAM metalloproteases promote a developmental switch in responsiveness to the axonal repellant Sema3A

Erez Romi, Irena Gokhman, Eitan Wong, Niv Antonovsky, Andreas Ludwig, Irit Sagi, Paul Saftig, Marc Tessier-Lavigne and Avraham Yaron ()
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Erez Romi: Weizmann Institute of Science
Irena Gokhman: Weizmann Institute of Science
Eitan Wong: Weizmann Institute of Science
Niv Antonovsky: Weizmann Institute of Science
Andreas Ludwig: Institute for Pharmacology and Toxicology, RWTH Aachen University
Irit Sagi: Weizmann Institute of Science
Paul Saftig: Institut fur Biochemie, Christian-Albrechts-Universität
Marc Tessier-Lavigne: Laboratory of Brain Development and Repair, Rockefeller University
Avraham Yaron: Weizmann Institute of Science

Nature Communications, 2014, vol. 5, issue 1, 1-15

Abstract: 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.

Date: 2014
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DOI: 10.1038/ncomms5058

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