Essential requirement for nicastrin in marginal zone and B-1 B cell development

Proc Natl Acad Sci U S A. 2020 Mar 3;117(9):4894-4901. doi: 10.1073/pnas.1916645117. Epub 2020 Feb 18.


γ-secretase is an intramembrane protease complex that catalyzes the proteolytic cleavage of amyloid precursor protein and Notch. Impaired γ-secretase function is associated with the development of Alzheimer's disease and familial acne inversa in humans. In a forward genetic screen of mice with N-ethyl-N-nitrosourea-induced mutations for defects in adaptive immunity, we identified animals within a single pedigree exhibiting both hypopigmentation of the fur and diminished T cell-independent (TI) antibody responses. The causative mutation was in Ncstn, an essential gene encoding the protein nicastrin (NCSTN), a member of the γ-secretase complex that functions to recruit substrates for proteolysis. The missense mutation severely limits the glycosylation of NCSTN to its mature form and impairs the integrity of the γ-secretase complex as well as its catalytic activity toward its substrate Notch, a critical regulator of B cell and T cell development. Strikingly, however, this missense mutation affects B cell development but not thymocyte or T cell development. The Ncstn allele uncovered in these studies reveals an essential requirement for NCSTN during the type 2 transitional-marginal zone precursor stage and peritoneal B-1 B cell development, the TI antibody response, fur pigmentation, and intestinal homeostasis in mice.

Keywords: B-1 B cells; T cell-independent antibody response; marginal zone B cells; nicastrin.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptive Immunity
  • Alzheimer Disease / metabolism
  • Amyloid Precursor Protein Secretases / metabolism*
  • Amyloid beta-Protein Precursor / genetics*
  • Amyloid beta-Protein Precursor / metabolism*
  • Animals
  • B-Lymphocyte Subsets / metabolism*
  • Cell Membrane / metabolism
  • Ethylnitrosourea / adverse effects
  • Female
  • Gene Expression Regulation, Developmental*
  • Hidradenitis Suppurativa / metabolism
  • Humans
  • Hypopigmentation
  • Male
  • Membrane Glycoproteins / genetics*
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mutation
  • Pedigree
  • T-Lymphocytes / metabolism
  • Transcriptome


  • Amyloid beta-Protein Precursor
  • Membrane Glycoproteins
  • nicastrin protein
  • Amyloid Precursor Protein Secretases
  • Ethylnitrosourea

Supplementary concepts

  • Hidradenitis suppurativa, familial