RESUMO
Mice homozygous for a disruption at the Lyn locus display abnormalities associated with the B lymphocyte lineage and in mast cell function. Despite reduced numbers of recirculating B lymphocytes, Lyn-/- mice are immunoglobulin M (IgM) hyperglobulinemic. Immune responses to T-independent and T-dependent antigens are affected. Lyn-/- mice fail to mediate an allergic response to IgE cross-linking, indicating that activation of LYN plays an indispensable role in Fc epsilon RI signaling. Lyn-/- mice have circulating autoreactive antibodies, and many show severe glomerulonephritis caused by the deposition of IgG immune complexes in the kidney, a pathology reminiscent of systemic lupus erythematosus. Collectively, these results implicate LYN as having an indispensable role in immunoglobulin-mediated signaling, particularly in establishing B cell tolerance.
Assuntos
Doenças Autoimunes/genética , Linfócitos B/patologia , Sistema Imunitário/anormalidades , Quinases da Família src/deficiência , Anafilaxia/imunologia , Animais , Formação de Anticorpos , Doenças Autoimunes/etiologia , Sequência de Bases , Glomerulonefrite/genética , Glomerulonefrite/imunologia , Imunoglobulina E/imunologia , Imunoglobulina M/sangue , Rim/patologia , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Camundongos , Camundongos Mutantes , Dados de Sequência Molecular , Quinases da Família src/genéticaRESUMO
The Lyn gene encodes a PTK that is believed to participate in the transduction of signals from a variety of cell membrane receptors. Here we report the genomic organisation of the mouse Lyn gene and show that, while the promoter and exons 11-13 are present in single copy, sequences corresponding to the first coding exon are duplicated and this duplication extends into intron 10. Two sets of genomic clones representing the duplicated regions have been isolated and characterised. Nucleotide sequence analysis of these clones has revealed minimal sequence divergence between the two, suggesting that the duplication is a recent event. This is supported by Southern blot analysis of DNA from other mammalian species showing that the duplication is confined to the mouse. Aside from the duplicated sequences, the overall structure of the mouse Lyn gene is similar to that of other Src family members. These data suggest that the process of duplication which generated the Src family of PTK is an ongoing process and provide an insight into the molecular evolution of this group of genes.
Assuntos
Família Multigênica , Proteínas Tirosina Quinases/genética , Quinases da Família src , Animais , Sequência de Bases , Evolução Biológica , Southern Blotting , Mapeamento Cromossômico , Expressão Gênica , Biblioteca Genômica , Humanos , Camundongos , Dados de Sequência Molecular , Splicing de RNA , Homologia de Sequência do Ácido Nucleico , Especificidade da EspécieRESUMO
The mutant mouse waved-2 (wa-2) is strikingly similar to transforming growth factor alpha-deficient mice generated by gene targeting in embryonic stem cells. We confirm that wa-2 is a point mutation (T-->G resulting in a valine-->glycine substitution at residue 743) in the gene encoding the epidermal growth factor (EGF) receptor. wa-2 fibroblastic cells lack high-affinity binding sites for EGF, and the rate of internalization of EGF is retarded. Although the tyrosine kinase activity of wa-2 EGF receptors is significantly impaired, NIH 3T3 cells lacking endogenous EGF receptors but overexpressing recombinant wa-2 EGF receptor cDNA are mitogenically responsive to EGF. While young and adult wa-2 mice are healthy and fertile, 35% of wa-2 mice born of homozygous wa-2 mothers die of malnutrition because of impaired maternal lactation.
