Human Molecular Genetics, 2002, Vol. 11, No. 21 2615-2624
© 2002 Oxford University Press
The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for 
-secretase activity in fibroblasts
1Center for Human Genetics KU Leuven and Flanders Interuniversity Institute for Biotechnology, VIB 4 and 2Department of Developmental Biology KU Leuven, VIB 7 (Celgen), Herestraat 49, 3000 Leuven, Belgium, 3Zentrum Biochemie und Molekulare Zellbiologie, Abteilung Biochemie II, Universität Göttingen, 37073 Göttingen, Germany and 4Biochemisches Institut der Christian-Albrecht-Universität Kiel, Olshausenstrasse 40, D-24118 Kiel, Germany
Received June 6, 2002; Accepted August 1, 2002
The metalloprotease ADAM 10 is an important APP 
-secretase candidate, but in vivo proof of this is lacking. Furthermore, invertebrate models point towards a key role of the ADAM 10 orthologues Kuzbanian and sup-17 in Notch signalling. In the mouse, this function is, however, currently attributed to ADAM 17/TACE, while the role of ADAM 10 remains unknown. We have created ADAM 10-deficient mice. They die at day 9.5 of embryogenesis with multiple defects of the developing central nervous system, somites, and cardiovascular system. In situ hybridization revealed a reduced expression of the Notch target gene hes-5 in the neural tube and an increased expression of the Notch ligand dll-1, supporting an important role for ADAM 10 in Notch signalling in the vertebrates as well. Since the early lethality precluded the establishment of primary neuronal cultures, APPs generation was analyzed in embryonic fibroblasts and found to be preserved in 15 out of 17 independently generated ADAM 10-deficient fibroblast cell lines, albeit at a quantitatively more variable level than in controls, whereas a severe reduction was found in only two cases. The variability was not due to differences in genetic background or to variable expression of the alternative -secretase candidates ADAM 9 and ADAM 17. These results indicate, therefore, either a regulation between ADAMs on the post-translational level or that other, not yet known, proteases are able to compensate for ADAM 10 deficiency. Thus, the observed variability, together with recent reports on tissue-specific expression patterns of ADAMs 9, 10 and 17, points to the existence of tissue-specific ‘teams’ of different proteases exerting -secretase activity.
* To whom correspondence should be addressed. Tel: +49 4318802216; Fax: +49 4318802238; Email: psaftig{at}biochem.uni-kiel.de
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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