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Regulation of EphA4 kinase activity is required for a subset of axon guidance decisions suggesting a key role for receptor clustering in Eph function

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • Joaquim Egea
  • Ulla Vig Nissen
  • Audrey Dufour
  • Mustafa Sahin
  • Paul Greer
  • Klas Kullander
  • Thomas D. Mrsic-Flogel
  • Michael E. Greenberg
  • Kiehn, Ole
  • Pierre Vanderhaeghen
  • Rüdiger Klein

Signaling by receptor tyrosine kinases (RTKs) is mediated by their intrinsic kinase activity. Typically, kinase-activating mutations result in ligand-independent signaling and gain-of-function phenotypes. Like other RTKs, Ephs require kinase activity to signal, but signaling by Ephs in vitro also requires clustering by their membrane bound ephrin ligands. The relative importance of Eph kinase activity and clustering for in vivo functions is unknown. We find that knockin mice expressing a mutant form of EphA4 (EphA4 EE), whose kinase is constitutively activated in the absence of ephrinB ligands, are deficient in the development of thalamocortical projections and some aspects of central pattern generator rhythmicity. Surprisingly, other functions of EphA4 were regulated normally by EphA4EE, including midline axon guidance, hindlimb locomotion, in vitro growth cone collapse, and phosphorylation of ephexin1. These results suggest that signaling of Eph RTKs follows a multistep process of induced kinase activity and higher-order clustering different from RTKs responding to soluble ligands.

OriginalsprogEngelsk
TidsskriftNeuron
Vol/bind47
Udgave nummer4
Sider (fra-til)515-528
Antal sider14
ISSN0896-6273
DOI
StatusUdgivet - 18 aug. 2005

ID: 194978709