A congenic strain of rat for investigation of control of estrogen-induced growth.
A congenic strain of rat for investigation of control of estrogen-induced growth.
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用于研究雌激素诱导生长控制的大鼠同源品系。
DOI：
10.1007/s00335-002-2183-6
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发表时间：
2002
期刊：
影响因子：
--
通讯作者：
Kelley,Parker
中科院分区：
文献类型：
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作者：
Wendell,DouglasL;Pandey,Jyotsna;Kelley,Parker
几十年来，大鼠垂体一直被用作模型系统来研究雌激素在肿瘤生长、细胞增殖和血管生成中的作用。使用大鼠垂体的一个主要原因是实验室大鼠品系之间在长期雌激素治疗对垂体肿瘤生长的影响方面存在巨大差异（Wiklund 和 Gorski 1982；Wendell 等人 1996；Spady 等人 1999）。例如，当近交系 Fischer 344 (F344) 的大鼠接受长期雌激素治疗时，垂体持续生长，在 8 周内达到正常质量的 10 倍以上 (Wiklund 和 Gorski 1982)。 F344 品系缺乏生长控制能力，而棕色挪威 (BN) 品系大鼠则能熟练控制雌激素刺激的垂体生长，并且在长期雌激素治疗后不会形成垂体肿瘤，甚至垂体质量也不会发生任何显着变化（Wendell 等，1996）。这种雌激素诱导的垂体肿瘤（因其过度生长而得名）表现出不受控制的细胞增殖，主要由泌乳素细胞组成（Phelps 和 Hymer 1983）。当大鼠连续几天服用雌激素时，抗肿瘤 Holtzman 大鼠的垂体细胞首先受到刺激增殖，但随后变得对激素产生抵抗（Wiklund 和 Gorski 1982）。这种顽固反应并不是由于对激素不敏感，因为垂体继续合成和释放催乳素（Wiklund et al. 1981）。因此，必须有一个特定于增长的主动负反馈机制。揭示肿瘤敏感菌株和抗肿瘤菌株之间差异的基础可以揭示正常细胞随后抑制生长的方式。 F344 和 BN 之间的生长控制差异是多基因的，并且归因于 BN 和 F344 之间的两代遗传杂交中至少有 6 个数量性状位点 (QTL)（Wendell 和 Gorski 1997）。 Edpm3（大鼠 Chr3 上的雌激素依赖性垂体质量 QTL）是在 F344 和 BN 的 F2 杂交中鉴定出的影响最大的 QTL（总表型方差的 16.6%）（Wendell 和 Gorski 1997），并已被选择用于进一步研究。 Edpm3 的 BN 等位基因与雌激素治疗大鼠垂体生长的控制相关，Edpm3 的 F344 等位基因的遗传与不受控制的雌激素依赖性生长相关（Wendell 和 Gorski 1997）。 为了研究 Edpm3 对控制雌激素依赖性生长的贡献，我们构建了一个同源品系，其中包含来自 BN 的 Edpm3 QTL 的大鼠 Chr3 片段基因渗入到F344菌株中。因此，该菌株对于 Edpm3 的 BN 等位基因是纯合的，但对于所有其他 QTL 的 F344 等位基因是纯合的。该同类品系是由现在标准的“速度同类”培育出来的
The rat pituitary has been used for several decades as a model system to investigate the role of estrogen in tumor growth, cell proliferation, and angiogenesis. A major reason for using the rat pituitary is the great difference between laboratory rat strains in the effect of chronic estrogen treatment on pituitary tumor growth (Wiklund and Gorski 1982; Wendell et al. 1996; Spady et al. 1999). For example, when rats of the inbred strain Fischer 344 (F344) are given a chronic estrogen treatment, the pituitary grows continuously to become over 10 times normal mass in 8 weeks (Wiklund and Gorski 1982). Whereas the F344 strain is deficient in growth control, the Brown Norway (BN) rat strain is proficient in the control of estrogen-stimulated pituitary growth and does not form a pituitary tumor, nor even any significant change in pituitary mass, upon chronic estrogen treatment (Wendell et al. 1996). This estrogen-induced pituitary tumor (so-called due to its excessive growth) exhibits uncontrolled cell proliferation and consists primarily of lactotrophs (Phelps and Hymer 1983). When rats are administered estrogen for several days, cells in the pituitary of tumor-resistant Holtzman rats are first stimulated to proliferate, but then become refractory to the hormone (Wiklund and Gorski 1982). This refractory response is not due to insensitivity to hormone, because the pituitary continues to synthesize and release prolactin (Wiklund et al. 1981). Thus, there must be an active negative feedback mechanism specific to growth. Uncovering the basis of the difference between tumor-susceptible and tumor-resistant strains can shed light on the means by which normal cells subsequently restrain growth. The difference in growth control between F344 and BN is polygenic and owing to at least six quantitative trait loci (QTL) that were mapped in two-generation genetic crosses between BN and F344 (Wendell and Gorski 1997). Edpm3 (estrogendependent pituitary mass QTL on rat Chr3) was the QTL with largest effect (16.6% of total phenotypic variance) identified in an F2 intercross between F344 and BN (Wendell and Gorski 1997) and has been selected for further study. The BN allele of Edpm3 correlates with control of pituitary growth in estrogentreated rats, and inheritance of the F344 allele of Edpm3 correlates with uncontrolled estrogen-dependent growth (Wendell and Gorski 1997).To investigate the contribution of Edpm3 to the control of estrogen-dependent growth, we constructed a congenic strain in which the segment of rat Chr3 containing the Edpm3 QTL from BN was introgressed into the F344 strain. Thus, this strain is homozygous for the BN allele of Edpm3, but homozygous for the F344 alleles of all other QTL. The congenic strain was bred by what is now the standard ‘‘speed congenic’’