Details

Autor(en) / Beteiligte

• Bonanomi, Dario
• Chivatakarn, Onanong
• Bai, Ge
• Abdesselem, Houari
• Lettieri, Karen
• Marquardt, Till
• Pierchala, Brian A.
• Pfaff, Samuel L.

Titel

Ret is a multifunctional co-receptor that integrates diffusible- and contact-axon guidance signals

Ist Teil von

• Cell, 2012-02, Vol.148 (3), p.568-582

Erscheinungsjahr

2012

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Growing axons encounter multiple guidance cues, but it is unclear how separate signals are resolved and integrated into coherent instructions for growth cone navigation. We report that glycosylphosphatidylinositol (GPI)-anchored ephrin-As function as “reverse” signaling receptors for motor axons when contacted by transmembrane EphAs present in the dorsal limb. Ephrin-A receptors are thought to depend on transmembrane co-receptors for transmitting signals intracellularly. We show that the receptor tyrosine kinase Ret is required for motor axon attraction mediated by ephrin-A reverse signaling. Ret also mediates GPI-anchored GFRα1 signaling in response to GDNF, a diffusible chemoattractant in the limb - indicating that Ret is a multifunctional co-receptor for guidance molecules. Axons respond synergistically to co-activation by GDNF and EphA ligands and these cooperative interactions are gated by GFRα1 levels. Our studies uncover a hierarchical GPI-receptor signaling network that is constructed from combinatorial components and integrated through Ret using ligand coincidence detection.