Journal
EMBO JOURNAL
Volume 30, Issue 11, Pages 2281-2293Publisher
WILEY
DOI: 10.1038/emboj.2011.136
Keywords
B-cell differentiation; Dll1; MT1-MMP; Notch signalling
Categories
Funding
- Research Grant Council of Hong Kong [HKU7513/03M, G_HK027/06, HKU781808M, HKU3/07C]
- CRCG fund [201007176204]
- National Science Foundation of China
- Ministry of Science and Technology of CHINA [2007CB50740, 2011CB964700]
- UGC
- Deutsche Forschungsgemeinschaft [SFB 829]
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Notch signalling controls the differentiation of haematopoietic progenitor cells (HPCs). Here, we show that loss of membrane-type 1 matrix metalloproteinase (MT1-MMP, MMP14), a cell surface protease expressed in bone marrow stromal cells (BMSCs), increases Notch signalling in HPCs and specifically impairs B-lymphocyte development. When co-cultured with BMSCs in vitro, HPCs differentiation towards B lymphocytes is significantly compromised on MT1-MMP-deficient BMSCs and this defect could be completely rescued by DAPT, a specific Notch signalling inhibitor. The defective B-lymphocyte development could also be largely rescued by DAPT in vivo. MT1-MMP interacts with Notch ligand Delta-like 1 (Dll1) and promotes its cleavage on cell surface in BMSCs. Ectopic MT1-MMP cleaves Dll1 and results in diminished Notch signalling in co-cultured cells. In addition, recombinant MT1-MMP cleaves a synthetic Dll1 peptide at the same site where MT1-MMP cleaves Dill on the cell surface. Our data suggest that MT1-MMP directly cleaves Dill on BMSCs to negatively regulate Notch signalling to specifically maintain normal B-cell development in bone marrow. The EMBO Journal (2011) 30, 2281-2293. doi:10.1038/emboj.2011.136; Published online 13 May 2011
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