title: Cyclin-dependent kinase inhibitor Cdkn2c regulates B cell homeostasis and function in the NZM2410-derived murine lupus susceptibility locus Sle2c1.
abstract: Sle2c1 is an NZM2410- and NZB-derived lupus susceptibility locus that induces an expansion of the B1a cell compartment. B1a cells have a repertoire enriched for autoreactivity, and an expansion of this B cell subset occurs in several mouse models of lupus. A combination of genetic mapping and candidate gene analysis presents Cdkn2c, a gene encoding for cyclin-dependent kinase inhibitor p18(INK4c) (p18), as the top candidate gene for inducing the Slec2c1-associated expansion of B1a cells. A novel single nucleotide polymorphism in the NZB allele of the Cdkn2c promoter is associated with a significantly reduced Cdkn2c expression in the splenic B cells and peritoneal cavity B1a cells from Sle2c1-carrying mice, which leads to a defective G1 cell cycle arrest in splenic B cells and increased proliferation of peritoneal cavity B1a cells. As the cell cycle is differentially regulated in B1a and B2 cells, these results suggest that Cdkn2c plays a critical role in B1a cell self-renewal and that its impaired expression leads to an accumulation of these cells with high autoreactive potential.
authors.affiliation: Department of Pathology, Immunology, and Laboratory Medicine, University of Florida, Gainesville, FL 32610, USA.
authors.forename: Zhiwei
authors.initials: Z
authors.lastname: Xu
authors.forename: Hari-Hara S K
authors.initials: HH
authors.lastname: Potula
authors.forename: Anusha
authors.initials: A
authors.lastname: Vallurupalli
authors.forename: Daniel
authors.initials: D
authors.lastname: Perry
authors.forename: Henry
authors.initials: H
authors.lastname: Baker
authors.forename: Byron P
authors.initials: BP
authors.lastname: Croker
authors.forename: Igor
authors.initials: I
authors.lastname: Dozmorov
authors.forename: Laurence
authors.initials: L
authors.lastname: Morel
mesh_terms: D000818:Animals; D015551:Autoimmunity / Q000235:genetics; D016175:B-Lymphocyte Subsets / Q000473:pathology; D001402:B-Lymphocytes / Q000166:cytology / Q000473:pathology* / Q000502:physiology; D002453:Cell Cycle; D049109:Cell Proliferation; D002874:Chromosome Mapping; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics / Q000502:physiology*; D004195:Disease Models, Animal; D056426:Genetic Loci / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006706:Homeostasis; D008180:Lupus Erythematosus, Systemic / Q000235:genetics / Q000473:pathology*; D018655:Lymphocyte Count; D051379:Mice; D020641:Polymorphism, Single Nucleotide
chemical_list: C493972:Cdkn2c protein, mouse; D050763:Cyclin-Dependent Kinase Inhibitor p18