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Title: The disintegrin/metalloprotease ADAM 10 is essential for Notch signalling but not for alpha-secretase activity in fibroblasts
Authors: Hartmann, Dieter ×
De Strooper, Bart
Serneels, Lutgarde
Craessaerts, Kathleen
Herreman, An
Annaert, Wim
Umans, Lieve
Lübke, Torben
Lena Illert, Anna
von Figura, Kurt
Saftig, Paul #
Issue Date: Oct-2002
Publisher: IRL Press
Series Title: Human Molecular Genetics vol:11 issue:21 pages:2615-24
Abstract: The metalloprotease ADAM 10 is an important APP alpha-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 alpha 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 alpha-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 alpha-secretase activity.
ISSN: 0964-6906
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Molecular Genetics Section (-)
Laboratory of Molecular Biology of Leukemia
Embryo and Stemcells (-)
Department of Human Genetics - miscellaneous
× corresponding author
# (joint) last author

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