Estrogen receptor null mice: what have we learned and where will they lead us?
Estrogen receptor null mice: what have we learned and where will they lead us?
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DOI：
10.1210/edrv.20.3.0370
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发表时间：
1999-06
影响因子：
20.3
通讯作者：
J. F. Couse;K. Korach
中科院分区：
文献类型：
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作者：
J. F. Couse;K. Korach
所有的科学研究开始都有明确的目标：第一个目标是提出假说，并在此基础上进行研究加以反驳;第二个目标是获得进一步的信息，从中可以得出未来更精确的假说。专注于基因靶向动物模型的生成和使用的研究也适用于这些目标，并且可以松散地分类为随着模型的使用而变得明显的连续阶段。敲除模型的初步研究通常集中在基于先验知识的模型的可验证性以及缺乏特定基因的动物的产生是否会被证明是致命的。在成功产生敲除后，进行验证性研究以证实先前建立的关于被破坏的基因产物的功能的假设。随着这些研究的继续，观察到不可预测的表型，或者更可能的是，缺乏基于过去研究提出的模型所预期的表型。通常，令人惊讶的表型是由于在被破坏的基因的功能下游的基因产物的损失，而缺乏预期的表型可能是由于由替代机制填补的补偿作用。随着对敲除的描述性研究的继续，模型的使用经常转变为作为独特的研究试剂的角色，用于以下研究：1）以前在野生型模型中不可能的; 2）旨在发现其存在或功能以前被掩盖的相关蛋白质或途径;或3）基因破坏对相关生理和生化系统的后续影响。α ERKO小鼠继续很好地满足敲除的确认作用。如表4中所总结的，由于雌激素不敏感性，在α ERKO中观察到的表型已经明确地说明了先前被认为依赖于功能性ER α的几种作用，包括1）对成年女性生殖道和乳腺的功能至关重要的增殖和分化作用; 2）作为子宫和乳腺中生长因子信号传导的必需组分; 3）作为主要的类固醇参与下丘脑-垂体轴中促性腺激素基因转录和LH水平的负调节; 4）作为几种组织中PR表达的正调节剂; 5）在垂体PRL合成和分泌的正调节中; 6）作为癌基因诱导的乳腺肿瘤的促进因子;（7）在雌性和雄性的几种行为的分化和激活中起着关键作用。α ERKO中不可预测的表型列表必须开始观察到缺乏功能性ER α基因的动物的产生是成功的，并且产生了表现出与野生型相当的寿命的两性动物。β ERKO小鼠的成功产生表明该受体对存活也不是必需的，并且很可能不是α ERKO存活的补偿因子。支持这一点的是我们最近成功的双敲除，或α β ERKO小鼠的两性。男性生殖的某些组成部分的精确缺陷，包括在α ERKO中观察到的异常精子的产生以及插入和射精反应的丧失，是相当令人惊讶的。反过来，α ERKO女性中的某些雌激素途径似乎完好无损或未受影响，例如子宫成功表现出孕酮诱导的蜕膜化反应的能力，以及下丘脑中LH峰系统的可能维持。[摘要截断]
All scientific investigations begin with distinct objectives: first is the hypothesis upon which studies are undertaken to disprove, and second is the overall aim of obtaining further information, from which future and more precise hypotheses may be drawn. Studies focusing on the generation and use of gene-targeted animal models also apply these goals and may be loosely categorized into sequential phases that become apparent as the use of the model progresses. Initial studies of knockout models often focus on the plausibility of the model based on prior knowledge and whether the generation of an animal lacking the particular gene will prove lethal or not. Upon the successful generation of a knockout, confirmatory studies are undertaken to corroborate previously established hypotheses of the function of the disrupted gene product. As these studies continue, observations of unpredicted phenotypes or, more likely, the lack of a phenotype that was expected based on models put forth from past investigations are noted. Often the surprising phenotype is due to the loss of a gene product that is downstream from the functions of the disrupted gene, whereas the lack of an expected phenotype may be due to compensatory roles filled by alternate mechanisms. As the descriptive studies of the knockout continue, use of the model is often shifted to the role as a unique research reagent, to be used in studies that 1) were not previously possible in a wild-type model; 2) aimed at finding related proteins or pathways whose existence or functions were previously masked; or 3) the subsequent effects of the gene disruption on related physiological and biochemical systems. The alpha ERKO mice continue to satisfy the confirmatory role of a knockout quite well. As summarized in Table 4, the phenotypes observed in the alpha ERKO due to estrogen insensitivity have definitively illustrated several roles that were previously believed to be dependent on functional ER alpha, including 1) the proliferative and differentiative actions critical to the function of the adult female reproductive tract and mammary gland; 2) as an obligatory component in growth factor signaling in the uterus and mammary gland; 3) as the principal steroid involved in negative regulation of gonadotropin gene transcription and LH levels in the hypothalamic-pituitary axis; 4) as a positive regulator of PR expression in several tissues; 5) in the positive regulation of PRL synthesis and secretion from the pituitary; 6) as a promotional factor in oncogene-induced mammary neoplasia; and 7) as a crucial component in the differentiation and activation of several behaviors in both the female and male. The list of unpredictable phenotypes in the alpha ERKO must begin with the observation that generation of an animal lacking a functional ER alpha gene was successful and produced animals of both sexes that exhibit a life span comparable to wild-type. The successful generation of beta ERKO mice suggests that this receptor is also not essential to survival and was most likely not a compensatory factor in the survival of the alpha ERKO. In support of this is our recent successful generation of double knockout, or alpha beta ERKO mice of both sexes. The precise defects in certain components of male reproduction, including the production of abnormal sperm and the loss of intromission and ejaculatory responses that were observed in the alpha ERKO, were quite surprising. In turn, certain estrogen pathways in the alpha ERKO female appear intact or unaffected, such as the ability of the uterus to successfully exhibit a progesterone-induced decidualization response, and the possible maintenance of an LH surge system in the hypothalamus. [ABSTRACT TRUNCATED]