Journal
NEURON
Volume 84, Issue 6, Pages 1258-1272Publisher
CELL PRESS
DOI: 10.1016/j.neuron.2014.11.004
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Funding
- Fondation pour la Recherche Medicale [DEQ20120323700]
- Agence Nationale de la Recherche (ANR) [ANR-08-MNP-030]
- French state funds [ANR-10-LABX-65]
- ANR within Investissements d'Avenir program [ANR-11-IDEX-0004-02]
- Region ile de France (Neuropole)
- Ecole des Neurosciences de Paris (ENP) Graduate Program fellowship from ENP
- Region Ile-de-France (DIM Cerveau et Pensee)
- Investissements d'Avenir program [ANR-10-LABX-54]
- Bristol-Myers Squibb Postdoctoral Fellowship at the Rockefeller University
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Development of neuronal circuits is controlled by evolutionarily conserved axon guidance molecules, including Slits, the repulsive ligands for roundabout (Robo) receptors, and Netrin-1, which mediates attraction through the DCC receptor. We discovered that the Robo3 receptor fundamentally changed its mechanism of action during mammalian evolution. Unlike other Robo receptors, mammalian Robo3 is not a high-affinity receptor for Slits because of specific substitutions in the first immunoglobulin domain. Instead, Netrin-1 selectively triggers phosphorylation of mammalian Robo3 via Src kinases. Robo3 does not bind Netrin-1 directly but interacts with DCC. Netrin-1 fails to attract pontine neurons lacking Robo3, and attraction can be restored in Robo3(-/-) mice by expression of mammalian, but not nonmammalian, Robo3. We propose that Robo3 evolution was key to sculpting the mammalian brain by converting a receptor for Slit repulsion into one that both silences Slit repulsion and potentiates Netrin attraction.
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