Silencing of the immunoglobulin heavy chain locus by removal of all eight constant-region genes in a 200-kb region

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• 作者：Ren ; Liming ; Zou ; Xiangang ; Smith ; Jennifer A. ; Br??ggemann ; Marianne
• 关键词：Immunoglobulin heavy chain locus ; Constant region genes ; B-cell development ; DNA rearrangement ; Transcription ; Gene silencing ; CreaaaloxP-mediated recombination ; Locus deletion ; Immunodeficiency
• 刊名：Genomics
• 出版年：2004
• 出版时间：October, 2004
• 年：2004
• 卷：84
• 期：4
• 页码：686-695
• 全文大小：545 K

文摘

Silencing or removal of individual C (constant)-region genes and/or adjacent control sequences did not generate fully deficient Ig (immunoglobulin)^aaa mice. A reason is that different C genes share many functional tasks and most importantly are individually capable of ensuring lymphocyte differentiation. Nevertheless, incomplete arrests in B-cell development were found, most pronounced at the onset of H-chain expression. Here we show that removal of 200 kb accommodating all C genes, CaaaaaCaaaaaCaa3aaaCaa1aaaCaa2baaaCaa2aaaaCaaaaaCaa, stops antibody production. For this two loxP targeting constructs were introduced into the most 5aaa C gene and the distal aa 3aaa enhancer. CreaaaloxP-mediated in vivo deletion was accompanied by extensive germ-line mosaicism, which could be separated by breeding. Homozygous C-gene deletion mice did not express Ig H or L chains and flow cytometry revealed a complete block in B-cell development. However, C-gene removal did not affect DNA rearrangement processes following locus activation, as recombination efficacy appears to be similar to what is found in normal mice.