Effects Of Luteinizing Hormone Receptor

人促黄体激素/绒毛膜促性腺激素受体（LHR）的组成型激活突变导致家族性男性限制性早熟（FMPP）。与乔治敦大学的Malcolm Martin博士和发育内分泌学分支的Ellen Leschek博士合作，我们确定了两名发生睾丸肿瘤的FPPP患者。为了研究LH/hCG信号通路的组成性激活对精子发生和性发育的影响，以及组成性激活的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。用活化LHR突变转染MA-10细胞。将表达突变的LHR的细胞中的表达基因的谱与对照细胞的表达基因的谱进行比较。对一种突变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，已知参与精子发生的几个基因在表达突变LHR的细胞中也下调。这项研究正在重复与不同的突变LHR基因的分析，采用更广泛的小鼠cDNA微阵列。我们正在构建携带激活突变的LHR构建体，用于引入小鼠ES细胞，以产生FMPP转基因动物模型，用于研究组成性激活的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.