Effects Of Luteinizing Hormone Receptor

人黄体生成素/绒毛膜促性腺激素受体（LHR）的组成性激活突变导致家族性男性限制性性早熟（FMPP）。我们与乔治城大学的Malcolm Martin博士和发育内分泌科的Ellen Leschek博士合作，确定了两名FMPP患者发展为睾丸肿瘤。为了研究LH/hCG信号通路组成性激活对精子发生和性发育的影响，以及组成性激活LHR的潜在致瘤作用，我们已经建立了体外细胞模型，并正在建立转基因动物模型。转染活化LHR突变的MA-10细胞。将表达突变LHR的细胞与对照细胞的表达基因谱进行比较。对一个突变LHR的初步研究表明，与细胞增殖相关的基因上调，与分化相关的基因下调。有趣的是，在表达突变LHR的细胞中，几个已知与精子发生有关的基因也被下调。利用更广泛的小鼠cDNA微阵列对不同突变的LHR基因进行了重复研究。我们正在构建携带激活突变的LHR基因构建体，并将其导入小鼠胚胎干细胞，构建FMPP转基因动物模型，以研究组成型激活LHR基因对精子发生和性发育的影响。

Constitutive activating mutations of the human Luteinizing hormone/chorionic gonadotropin hormone receptor (LHR) causes familial male-limited precocious puberty (FMPP). In collaboration with Dr. Malcolm Martin, Georgetown University, and Dr. Ellen Leschek, Developmental Endocrinology Branch, we have identified two FMPP patients who developed testicular neoplasia. To study the impact of constitutive activation of the LH/hCG signaling pathway on spermatogenesis and sexual development, and the potential tumorigenic effect of a constitutively activated LHR, we have generated an in vitro cell model and are in the process of generating a transgenic animal model. MA-10 cells were transfected with activating LHR mutations. The profile of expressed genes in cells expressing the mutated LHR was compared with that of control cells. Preliminary studies of one mutated LHR indicated up-regulation of genes associated with cell proliferation and down-regulation of genes associated with differentiation. Interestingly, several genes known to be involved in spermatogenesis were also down-regulated in cells expressing the mutated LHR. This study is being repeated with different mutated LHR genes with analysis employing a more extensive mouse cDNA microarray. We are generating constructs of LHR carrying activating mutations for introduction into mouse ES cells to generate a transgenic animal model of FMPP for the study of the impact of constitutively activated LHR gene on spermatogenesis and sexual development.