A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development

• Published in: Nature neuroscience Vol. 15; no. 12; pp. 1645 - 1654
• Main Authors: Soskis, Michael J, Ho, Hsin-Yi Henry, Bloodgood, Brenda L, Robichaux, Michael A, Malik, Athar N, Ataman, Bulent, Rubin, Alex A, Zieg, Janine, Zhang, Chao, Shokat, Kevan M, Sharma, Nikhil, Cowan, Christopher W, Greenberg, Michael E
• Format: Journal Article
• Language: English
• Published: United States Nature Publishing Group 01.12.2012
• Subjects: Alzheimer's disease; Amino Acid Sequence; Animals; Axons; Brain; Brain - embryology; Brain - physiology; Brain Chemistry - genetics; Brain Chemistry - physiology; Cells, Cultured; Female; Gene Knock-In Techniques; Genetic aspects; HEK293 Cells; Humans; Kinases; Ligands; Mice; Mice, 129 Strain; Mice, Inbred C57BL; Mice, Transgenic; Molecular Sequence Data; Nervous system; Neurosciences; Organ Culture Techniques; Phosphorylation; Phosphotransferases; Physiological aspects; Pregnancy; Protein Engineering - methods; Proteins; Rats; Receptors, Eph Family - genetics; Receptors, Eph Family - physiology; Signal Transduction - physiology; Synapses; Systems development; United States; United States > US; Massachusetts; California
• ISSN: 1097-6256; 1546-1726
• DOI: 10.1038/nn.3249

EphB receptor tyrosine kinases control multiple steps in nervous system development. However, it remains unclear whether EphBs regulate these different developmental processes directly or indirectly. In addition, given that EphBs signal through multiple mechanisms, it has been challenging to define which signaling functions of EphBs regulate particular developmental events. To address these issues, we engineered triple knock-in mice in which the kinase activity of three neuronally expressed EphBs can be rapidly, reversibly and specifically blocked. We found that the tyrosine kinase activity of EphBs was required for axon guidance in vivo. In contrast, EphB-mediated synaptogenesis occurred normally when the kinase activity of EphBs was inhibited, suggesting that EphBs mediate synapse development by an EphB tyrosine kinase-independent mechanism. Taken together, our data indicate that EphBs control axon guidance and synaptogenesis by distinct mechanisms and provide a new mouse model for dissecting EphB function in development and disease.