重組激活基因(recombination．a(chǎn)ctivating genes，Rags)在V(D)J重組過程中發(fā)揮重要作用，V(D)J重組過程中發(fā)生的免疫球蛋白(Ig)基因和T細(xì)胞受體(TCR)基因的重排和重組是B細(xì)胞和T淋巴細(xì)胞成熟過程中的必需階段。 小鼠的兩個重組激活基因Rag1和Rag2均位于2號染色體，其編碼的Rag1和Rag2蛋白在成熟前T細(xì)胞發(fā)育成為成熟T細(xì)胞以及成熟前B細(xì)胞發(fā)育成為成熟B細(xì)胞的過程中，通過識別Ig或TCR基因，并結(jié)合基因片段中的重組信號序列(RSS)，啟動V(D)J重組。 Rag1和Rag2在淋巴細(xì)胞V(D)J重排過程中缺一不可，任意一個缺失都會導(dǎo)致T、B淋巴細(xì)胞發(fā)育中斷，表現(xiàn)為嚴(yán)重的T／B細(xì)胞早期發(fā)育阻滯，T細(xì)胞停滯在CD3-CD4-CD8+CD25+階段，B細(xì)胞停滯在B220-CD43+IgM-階段，進(jìn)而不能產(chǎn)生成熟的T、B淋巴細(xì)胞。因外周血中沒有成熟T/B淋巴細(xì)胞，導(dǎo)致機體產(chǎn)生與人“重癥聯(lián)合免疫缺陷癥”(severe combined immunodeficiency，SCID)類似的癥狀。 Rag1或者Rag2基因缺陷的小鼠外觀發(fā)育正常，具有正常生殖能力，但由于不能產(chǎn)生T、B淋巴細(xì)胞，無法對異體來源的細(xì)胞產(chǎn)生異體排斥，因而可以作為移植瘤模型的載體。 在Rag1基因ATG位點定點敲入loxP-EGFP-PolyA-loxP-Neo-loxP表達(dá)框，從而造成Rag1基因沉默。作為Rag1基因敲除小鼠，皮下接種肝癌組織塊和腫瘤細(xì)胞后能形成腫瘤，并且可以增長。由FACS檢測小鼠外周靜脈血中的T、B淋巴細(xì)胞生成量極低，與Nude小鼠T、B淋巴細(xì)胞產(chǎn)生量相當(dāng)甚至更低，與野生型小鼠相比具有顯著性差異。腫瘤組織HE染色病理切片結(jié)果顯示Rag1 KO小鼠和Nude小鼠腫瘤切片較為相似。該品系小鼠具有替代Nude，NOD-SCID小鼠作為腫瘤成瘤模型的潛力。

Fig.1 Construction strategy of Rag1-KO.

Fig.2?Loss of T and B cells in peripheral blood of Rag1-KO and Rag2-KO mice.

Fig.3 Loss of T and B cells in Spleen of Rag1-KO and Rag2-KO mice.

Fig.4 Loss of T and B cells in thymus of Rag1-KO and Rag2-KO mice.

Fig.5 Detection of EGFP expression in CD45+ cells in spleen, blood, thymus, and bone marrow of 8.7-week-old female WT and HO Rag1-KO(Rag1-EGFP) mice.

Fig.6 Detection of mouse IgG(A) and IgM(B) expression in serum by ELISA. (male, 5~6wks, n=3)

Abbr. HO, homozygous; WT, wild type; N.D. not detected.

Fig.7 Tumorigenicity results following inoculation with A549 tumor cells in Balb/c nude, NOD-Scid, Rag1-KO and Rag2-KO mice.

Table1. Complete blood count of Rag1-KO (Rag1-EGFP) mice

Table 2. Serum biochemical analysis of Rag1-KO (Rag1-EGFP) mice.

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