Crossing the SJL lambda locus into kappa-knockout mice reveals a dysfunction of the lambda 1-containing immunoglobulin receptor in B cell differentiation.
Mice of the SJL strain produce approximately 50 times less serum lambda 1 immunoglobulin light chains than other mouse strains. The defect is genetically linked to the lambda locus, but it is unknown whether it is due to regulatory alterations or known structural changes. We find no mutation in the SJL lambda 3-1 enhancer which regulates both lambda 1 and lambda 3. To investigate the defect further, the production of lambda light chains was amplified by crossing SJL with kappa-knockout mice. In kappa-knockout mice with the wildtype lambda locus (kappa -/- lambda +/+), the majority of serum light chains are lambda 1. In contrast, kappa-knockout mice with the SJL lambda locus (kappa -/- lambda s/s) show a pronounced expression of lambda 2 and lambda 3, with only some expression of lambda 1. The results show that the SJL defect is lambda 1 specific, since the linked lambda 3 expression is normal. As the transcription and rearrangement of lambda 1 appear normal in SJL, the defective lambda 1 synthesis is most likely due to a point mutation in the lambda 1 constant region resulting in a glycine to valine substitution. At the cellular level, in kappa-knockout mice with the SJL lambda locus there are fewer immature, and especially mature, lambda 1 B cells and the production of lambda 1 plasma cells is strongly inhibited. The lambda 1 specificity of the defect suggests that the point mutation in SJL C lambda 1 creates an immunoglobulin receptor complex which is dysfunctional in B cell differentiation.
Kim
J Y
JY
Department of Molecular Genetics and Cell Biology, University of Chicago, IL 60637.
Kurtz
B
B
Huszar
D
D
Storb
U
U
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology* / Q000378:metabolism; D001483:Base Sequence; D001854:Bone Marrow Cells; D002454:Cell Differentiation / Q000276:immunology; D002469:Cell Separation; D002874:Chromosome Mapping; D003433:Crosses, Genetic; D017931:DNA Primers; D004742:Enhancer Elements, Genetic; D005434:Flow Cytometry; D015328:Gene Rearrangement, B-Lymphocyte, Light Chain; D006720:Homozygote; D006825:Hybridomas; D007146:Immunoglobulin lambda-Chains / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D008969:Molecular Sequence Data; D017354:Point Mutation; D012333:RNA, Messenger / Q000378:metabolism; D011971:Receptors, Immunologic / Q000235:genetics* / Q000502:physiology; D013154:Spleen / Q000166:cytology
D017931:DNA Primers; D007146:Immunoglobulin lambda-Chains; D012333:RNA, Messenger; D011971:Receptors, Immunologic