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Molecular and Cellular Biology, December 2007, p. 8797-8806, Vol. 27, No. 24
0270-7306/07/$08.00+0     doi:10.1128/MCB.01355-07
Copyright © 2007, American Society for Microbiology. All Rights Reserved.

Haploinsufficiency of c-Met in cd44^–/– Mice Identifies a Collaboration of CD44 and c-Met In Vivo

Forschungszentrum Karlsruhe, Institute for Toxicology and Genetics, Postfach 3640, 76021 Karlsruhe, Germany,¹ Department of Neurophysiology and DFG-Research Center of Molecular Physiology of Brain, University of Göttingen, Humboldtallee 23, 37073 Göttingen, Germany,² Institute for Clinical Neurobiology, University of Würzburg, Josef Schneider Strasse 11, 97080 Würzburg, Germany,³ Institute of Anatomy and Cell Biology, University of Würzburg, Koellikerstrasse 6, 97070 Würzburg, Germany⁴

Received 27 July 2007/ Accepted 27 September 2007

Recent evidence has shown that the activation of receptor tyrosine kinases is not only dependent on binding of their ligands but in addition requires adhesion molecules as coreceptors. We have identified CD44v6 as a coreceptor for c-Met in several tumor and primary cells. The CD44v6 ectodomain is required for c-Met activation, whereas the cytoplasmic tail recruits ERM proteins and the cytoskeleton into a signalosome complex. Here we demonstrate that c-Met (and hepatocyte growth factor and Gab1) is haploinsufficient in a cd44^–/– background, as the cd44^–/–; met^+/– (and cd44^–/–; hgf^+/– and cd44^–/–; gab1^+/–) mice die at birth. They have impaired synaptic transmission in the respiratory rhythm-generating network and alterations in the phrenic nerve. These results are the first genetic data showing that CD44 and c-Met collaborate in vivo and that they are involved in synaptogenesis and axon myelination in the central and peripheral nervous systems.

Published ahead of print on 8 October 2007.