Regulation of repulsion versus adhesion by different splice forms of an Eph receptor

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Abstract

Eph tyrosine kinase receptors and their membrane-bound ephrin ligands mediate cell interactions and participate in several developmental processes1,2,3,4. Ligand binding to an Eph receptor results in tyrosine phosphorylation of the kinase domain, and repulsion of axonal growth cones and migrating cells. Here we report that a subpopulation of ephrin-A5 null mice display neural tube defects resembling anencephaly in man. This is caused by the failure of the neural folds to fuse in the dorsal midline, suggesting that ephrin-A5, in addition to its involvement in cell repulsion5,6, can participate in cell adhesion. During neurulation, ephrin-A5 is co-expressed with its cognate receptor EphA7 in cells at the edges of the dorsal neural folds. Three different EphA7 splice variants7,8, a full-length form and two truncated versions lacking kinase domains, are expressed in the neural folds. Co-expression of an endogenously expressed truncated form of EphA7 suppresses tyrosine phosphorylation of the full-length EphA7 receptor and shifts the cellular response from repulsion to adhesion in vitro. We conclude that alternative usage of different splice forms of a tyrosine kinase receptor can mediate cellular adhesion or repulsion during embryonic development.

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Figure 1: Neural tube defects in ephrin-A5 null mice.
Figure 2: Ephrin-A5 and EphA7 splice versions in cell adhesion and migration.
Figure 3: Regulation of repulsion versus adhesion by different EphA7 splice forms.
Figure 4: EphA7-T1 suppresses tyrosine phosphorylation of EphA7-FL.

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Acknowledgements

We thank M. Barbacid, J. Ericson, J. Flanagan, U. Lendahl, B. Öbrink, L. Philipson, D. Wilkinson and members of our laboratory for helpful discussions; S. Park for help with vector construction; T. Ciossek for EphA7 cDNAs and antisera; J. Wasserman for assistance with scanning electron miscroscopy; and B. Singer and G. Greicius for help with FACS analysis. This study was supported by grants from the Swedish Foundation for Strategic Research, the Karolinska Institute, the Swedish Medical Research Council, the Swedish Cancer Society, the Swedish Medical Society, Hedlunds stiftelse, Ostermans stiftelse, Magnus Bergvalls stiftelse, Marcus Borgströms stiftelse, Hagbergs stiftelse, Tore Nilssons stiftelse, the Wenner-Gren foundation, Åke Wibergs stiftelse and Kapten Arthur Erikssons fond. D.L.C. was supported by a Wenner-Gren postdoctoral fellowship.

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Correspondence to Jonas Frisén.

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