ADAM10 is essential for Notch2-dependent marginal zone B cell development and CD23 cleavage in vivo
Year: 2010
Type: article
Abstract: The proteolytic activity of a disintegrin and metalloproteinase 10 (ADAM10) regulates cell-fate decisions in Drosophila and mouse embryos. However, in utero lethality of ADAM10(-/-) mice has prevented examination of ADAM10 cleavage events in lymphocytes. To investigate their role in B cell development, we generated B cell-specific ADAM10 knockout mice. Intriguingly, deletion of ADAM10 prevented development of the entire marginal zone B cell (MZB) lineage. Additionally, cleavage of the low affinity IgE receptor, CD23, was profoundly impaired, but subsequent experiments demonstrated that ADAM10 regulates CD23 cleavage and MZB development by independent mechanisms. Development of MZBs is dependent on Notch2 signaling, which requires proteolysis of the Notch2 receptor by a previously unidentified proteinase. Further experiments revealed that Notch2 signaling is severely impaired in ADAM10-null B cells. Thus, ADAM10 critically regulates MZB development by initiating Notch2 signaling. This study identifies ADAM10 as the in vivo CD23 sheddase and an important regulator of B cell development. Moreover, it has important implications for the treatment of numerous CD23- and Notch-mediated pathologies, ranging from allergy to cancer.
DOI: 10.1084/jem.20091990
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: bronze
Funders: American Heart Association, Crohn's and Colitis Foundation of America, Virginia Commonwealth University, Crohn's and Colitis Foundation, National Institutes of Health, National Cancer Institute, National Institute of Allergy and Infectious Diseases, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute of Neurological Disorders and Stroke
Awards: Structure and Function of the B Lymphocyte FCe Receptor, Pancreatic Tumor Progression in the Absence of ADAM-mediated alpha-secretase Acti, VCU Neuroscience Center Core Grant, Cellular & Inflammatory Pathways in Ashtma & Allergic Diseases: From IgE to Cells, ADAM17 in pancreatic cancer and pancreatitis, G5948588482, Endogenous Betacellulin Signaling in Beta-cell Biology
OpenAlex ID: W2159110897