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First published online 11 October 2006
doi: 10.1242/dev.02623

Development 133, 4415-4420 (2006)
Published by The Company of Biologists 2006
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Research Report

Genetic analysis of EphA-dependent signaling mechanisms controlling topographic mapping in vivo

Audrey Dufour1, Joaquim Egea2, Klas Kullander3, Rüdiger Klein2 and Pierre Vanderhaeghen1,*

1 Institut de Recherches en Biologie Humaine et Moléculaire (IRIBHM), University of Brussels (U.L.B.), Campus Erasme, 808 Route de Lennik, B-1070 Brussels, Belgium.
2 Max Planck Institute of Neurobiology, 82152 Martinsried, Germany.
3 Department of Neuroscience, Unit of Developmental Genetics, Uppsala University, Box 587, 751 23 Uppsala, Sweden.

* Author for correspondence (e-mail: pvdhaegh{at}ulb.ac.be)

Accepted 11 September 2006

SUMMARY

Ephrin/Eph ligands and receptors are best known for their prominent role in topographic mapping of neural connectivity. Despite the large amount of work centered on ephrin/Eph-dependent signaling pathways in various cellular contexts, the molecular mechanisms of action of Eph receptors in neural mapping, requiring dynamic interactions between complementary gradients of ephrins and Eph receptors, remain largely unknown. Here, we investigated in vivo the signaling mechanisms of neural mapping mediated by the EphA4 receptor, previously shown to control topographic specificity of thalamocortical axons in the mouse somatosensory system. Using axon tracing analyses of knock-in mouse lines displaying selective mutations for the Epha4 gene, we determined for the first time which intracellular domains of an Eph receptor are required for topographic mapping. We provide direct in vivo evidence that the tyrosine kinase domain of EphA4, as well as a tight regulation of its activity, are required for topographic mapping of thalamocortical axons, whereas non-catalytic functional modules, such as the PDZ-binding motif (PBM) and the Sterile-{alpha} motif (SAM) domain, are dispensable. These data provide a novel insight into the molecular mechanisms of topographic mapping, and constitute a physiological framework for the dissection of the downstream signaling cascades involved.

Key words: Topographic mapping, Ephrin, Eph, Thalamocortical




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