The Luteinizing Hormone Receptor Knockout Mouse as a Tool to Probe the In Vivo Actions of Gonadotropic Hormones/Receptors in Females.
The Luteinizing Hormone Receptor Knockout Mouse as a Tool to Probe the In Vivo Actions of Gonadotropic Hormones/Receptors in Females.
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DOI：
10.1210/endocr/bqab035
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发表时间：
2021-05-01
期刊：
影响因子：
4.8
通讯作者：
Huhtaniemi I
中科院分区：
文献类型：
--
作者：
Jonas KC;Rivero Müller A;Oduwole O;Peltoketo H;Huhtaniemi I
促性腺激素功能改变的小鼠模型为这些激素/受体的功能提供了宝贵的见解。在这里，我们描述了不育和性腺功能减退的促黄体生成激素受体（LHR）基因敲除小鼠模型（LuRKO）的再利用，以解决生殖生理学中的突出问题。使用杂交策略以及生理和组织学分析，我们首先分别使用2种配体结合和信号传导缺陷突变体LHR的BAC表达来解决雌性小鼠中强制LHR同质化的生理相关性，这些突变体之前已被证明进行功能互补并拯救雄性LuRKO小鼠的性腺功能减退表型。在雌性LuRKO小鼠中，信号传导和结合缺陷型LHR突变体的共表达未能挽救性腺功能减退和无排卵表型。这显然是由于低水平表达的2突变LHR和潜在的缺乏促黄体生成激素（LH）/LHR依赖性多效性信号，先前已被证明在高受体密度是排卵所必需的。接下来，我们利用过表达人绒毛膜促性腺激素（hCG）的小鼠模型，其循环“LH/hCG”样生物活性增加至WT雌性的约40倍，以确定LuRKO背景下的高循环hCG是否可以揭示推定的LHR非依赖性作用。未发现任何影响，因此，表明LH/hCG仅通过LHR介导其性腺和非性腺效应。最后，有针对性地表达一种组成型活性促卵泡激素受体（FSHR），使有腔卵泡进展为排卵前卵泡，并显示增强雌激素活性的表型标记，但未能诱导LuRKO小鼠排卵。这项研究强调了功能性LHR和FSHR介导卵巢功能的关键重要性和精确控制，以及现有转基因小鼠模型在回答生殖生理学中悬而未决的问题时的潜在再利用。
Mouse models with altered gonadotropin functions have provided invaluable insight into the functions of these hormones/receptors. Here we describe the repurposing of the infertile and hypogonadal luteinizing hormone receptor (LHR) knockout mouse model (LuRKO), to address outstanding questions in reproductive physiology. Using crossbreeding strategies and physiological and histological analyses, we first addressed the physiological relevance of forced LHR homomerization in female mice using BAC expression of 2 ligand-binding and signaling deficient mutant LHR, respectively, that have previously shown to undergo functional complementation and rescue the hypogonadal phenotype of male LuRKO mice. In female LuRKO mice, coexpression of signaling and binding deficient LHR mutants failed to rescue the hypogonadal and anovulatory phenotype. This was apparently due to the low-level expression of the 2 mutant LHR and potential lack of luteinizing hormone (LH)/LHR-dependent pleiotropic signaling that has previously been shown at high receptor densities to be essential for ovulation. Next, we utilized a mouse model overexpressing human chorionic gonadotropin (hCG) with increased circulating “LH/hCG”-like bioactivity to ~40 fold higher than WT females, to determine if high circulating hCG in the LuRKO background could reveal putative LHR-independent actions. No effects were found, thus, suggesting that LH/hCG mediate their gonadal and non-gonadal effects solely via LHR. Finally, targeted expression of a constitutively active follicle stimulating hormone receptor (FSHR) progressed antral follicles to preovulatory follicles and displayed phenotypic markers of enhanced estrogenic activity but failed to induce ovulation in LuRKO mice. This study highlights the critical importance and precise control of functional LHR and FSHR for mediating ovarian functions and of the potential repurposing of existing genetically modified mouse models in answering outstanding questions in reproductive physiology.
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DOI：
10.1073/pnas.0404743101
发表时间：
2004-12-07
影响因子：
11.1
作者：
Ma, XP;Dong, YL;Kumar, TR
通讯作者：
Kumar, TR
DOI：
10.1073/pnas.95.23.13612
发表时间：
1998-11-10
影响因子：
11.1
作者：
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通讯作者：
Sassone-Corsi, P
影响因子：
4.8
作者：
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通讯作者：
Murphy, Bruce D.
影响因子：
5.3
作者：
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Conti, Marco
影响因子：
4.8
作者：
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HSUEH, AJW