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

Michael J. Soskis, Hsin-Yi Henry Ho, Brenda L. Bloodgood, Michael A. Robichaux, Athar N. Malik, Bulent Ataman, Alex A. Rubin, Janine Zieg, Chao Zhang, Kevan M. Shokat, Nikhil Sharma, Christopher W. Cowan, Michael E. Greenberg

Research output: Contribution to journalArticle

19 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1645-1654
Number of pages10
JournalNature Neuroscience
Volume15
Issue number12
DOIs
StatePublished - Dec 2012
Externally publishedYes

ASJC Scopus subject areas

  • Neuroscience(all)

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    Soskis, M. J., Ho, H-Y. H., Bloodgood, B. L., Robichaux, M. A., Malik, A. N., Ataman, B., Rubin, A. A., Zieg, J., Zhang, C., Shokat, K. M., Sharma, N., Cowan, C. W., & Greenberg, M. E. (2012). A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development. Nature Neuroscience, 15(12), 1645-1654. https://doi.org/10.1038/nn.3249