title: A chemical genetic approach reveals distinct EphB signaling mechanisms during brain development.
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.
authors.affiliation: Department of Neurobiology, Harvard Medical School, Boston, Massachusetts, USA.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Soskis
authors.forename: Hsin-Yi Henry
authors.initials: HY
authors.lastname: Ho
authors.forename: Brenda L
authors.initials: BL
authors.lastname: Bloodgood
authors.forename: Michael A
authors.initials: MA
authors.lastname: Robichaux
authors.forename: Athar N
authors.initials: AN
authors.lastname: Malik
authors.forename: Bulent
authors.initials: B
authors.lastname: Ataman
authors.forename: Alex A
authors.initials: AA
authors.lastname: Rubin
authors.forename: Janine
authors.initials: J
authors.lastname: Zieg
authors.forename: Chao
authors.initials: C
authors.lastname: Zhang
authors.forename: Kevan M
authors.initials: KM
authors.lastname: Shokat
authors.forename: Nikhil
authors.initials: N
authors.lastname: Sharma
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Cowan
authors.forename: Michael E
authors.initials: ME
authors.lastname: Greenberg
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000196:embryology* / Q000502:physiology*; D001923:Brain Chemistry / Q000235:genetics* / Q000502:physiology; D002478:Cells, Cultured; D005260:Female; D055879:Gene Knock-In Techniques; D057809:HEK293 Cells; D006801:Humans; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D009924:Organ Culture Techniques; D011247:Pregnancy; D015202:Protein Engineering / Q000379:methods*; D051381:Rats; D036081:Receptors, Eph Family / Q000235:genetics* / Q000502:physiology; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D036081:Receptors, Eph Family