TY - JOUR
T1 - A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development
AU - Soskis, Michael J.
AU - Ho, Hsin-Yi Henry
AU - Bloodgood, Brenda L.
AU - Robichaux, Michael A.
AU - Malik, Athar N.
AU - Ataman, Bulent
AU - Rubin, Alex A.
AU - Zieg, Janine
AU - Zhang, Chao
AU - Shokat, Kevan M.
AU - Sharma, Nikhil
AU - Cowan, Christopher W.
AU - Greenberg, Michael E.
PY - 2012/12
Y1 - 2012/12
N2 - 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.
AB - 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.
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U2 - 10.1038/nn.3249
DO - 10.1038/nn.3249
M3 - Article
C2 - 23143520
AN - SCOPUS:84870518549
VL - 15
SP - 1645
EP - 1654
JO - Nature Neuroscience
JF - Nature Neuroscience
SN - 1097-6256
IS - 12
ER -