International Immunology Advance Access originally published online on July 17, 2008
International Immunology 2008 20(9):1181-1187; doi:10.1093/intimm/dxn076
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ADAM10 is essential for proteolytic activation of Notch during thymocyte development
1 Institute of Developmental Biology and Molecular Medicine, School of Life Sciences, Fudan University, Shanghai 200433, China
2 Department of Molecular, Cellular, and Developmental Biology, Howard Hughes Medical Institute, University of Colorado, Boulder, CO 80309-0347, USA
3 Department of Genetics, Howard Hughes Medical Institute, Yale University School of Medicine, New Haven, Connecticut, CT 06536, USA
4 Department of Immunology, Duke University Medical Center, Durham, NC 27701, USA
Correspondence to: Y. Zhuang; E-mail: yzhuang{at}duke.edu
Notch signaling pathway has been shown to play essential roles in T lymphocyte development. Activation of Notch requires a sequential proteolytic cleavage, which converts Notch from the full-length membrane-bound form to a transcriptionally active intracellular fragment. Studies in Drosophila showed that Kuzbanian (Kuz) is responsible for the enzymatic cleavage of extracellular S2 site upon Notch binding to its ligand Delta. Both a disintegrin and metalloprotease (ADAM) 10 and ADAM17, members of the ADAM family metalloproteases, have been indicated as the mammalian counterpart of Kuz in activating Notch in mammals. Here, we investigated functions of ADAM10 in Notch signaling during thymocyte development. We show that conditional disruption of the Adam10 gene in mouse thymocytes results in a developmental defect similar to the phenotypes previously described for T lineage-specific disruption of Notch1. We further show that the activation of Notch1 and its downstream target genes Deltex-1 and Pre-Ta are impaired in Adam10-deficient thymocytes. Our study demonstrates a T cell intrinsic role for Adam10 in activation of Notch1 during thymocyte development.
Keywords: cre, Kuzbanian, metalloprotease, thymus
Transmitting editor: P. W. Kincade
Received 1 February 2008, accepted 10 June 2008.
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