Essential requirement for nicastrin in marginal zone and B-1 B cell development
Jin Huk Choi, Jonghee Han, Panayotis C. Theodoropoulos, Xue Zhong, Jianhui Wang, Dawson Medler, Sara Ludwig, Xiaoming Zhan, Xiaohong Li, Miao Tang, T. F. Gallagher, Gang Yu, Bruce Beutler
Abstract
Significance Follicular B cells generally require T cell help to contribute to adaptive immunity, producing several isotypes of immunoglobulins that carry out distinct effector functions. Two specialized B cell subsets, marginal zone (MZ) and B-1 B cells, arise from different developmental steps and have different functions. They become activated to produce antibodies without T cell help and are the major sources of plasma IgM. We identified a viable missense allele of Ncstn in a forward genetic screen. We discovered that the development of MZ and B-1 B cells, TI antibody response, fur pigmentation, and intestinal homeostasis critically depend on the glycosylation status of NCSTN and the catalytic activity of γ-secretase toward its substrate Notch, a critical receptor in numerous developmental decisions.