Signaling Switch of the Axon Guidance Receptor Robo3 during Vertebrate Evolution

Archive ouverte

Zelina, Pavol | Blockus, Heike | Zagar, Yvrick | Péres, Amélie | Friocourt, François | Wu, Zhuhao | Rama, Nicolas | Fouquet, Coralie | Hohenester, Erhard | Tessier-Lavigne, Marc | Schweitzer, Jörn | Roest Crollius, Hugues | Chédotal, Alain

Edité par CCSD ; Elsevier -

International audience. 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.

• Description
• Sujet/Public
• Outil
• Outil d'anticipation
• Mémoire et thèse
• Gestion