Departments of Cellular and Integrative Physiology, Indiana University-Purdue University, Indianapolis, IN 46202, USA.
Endocrinology. 2013 Feb;154(2):738-48. doi: 10.1210/en.2012-1790. Epub 2013 Jan 3.
Combined pituitary hormone deficiency (CPHD) diseases result in severe outcomes for patients including short stature, developmental delays, and reproductive deficiencies. Little is known about their etiology, especially the developmental profiles and the influences of genetic background on disease progression. Animal models for CPHD provide valuable tools to investigate disease mechanisms and inform diagnostic and treatment protocols. Here we examined hormone production during pituitary development and the influence of genetic background on phenotypic severity in the Lhx3(W227ter/W227ter) mouse model. Lhx3(W227ter/W227ter) embryos have deficiencies of ACTH, α-glycoprotein subunit, GH, PRL, TSHβ, and LHβ during prenatal development. Furthermore, mutant mice have significant reduction in the critical pituitary transcriptional activator-1 (PIT1). Through breeding, the Lhx3(W227ter/W227ter) genotype was placed onto the 129/Sv and C57BL/6 backgrounds. Intriguingly, the genetic background significantly affected viability: whereas Lhx3(W227ter/W227ter) animals were found in the expected frequencies in C57BL/6, homozygous animals were not viable in the 129/Sv genetic environment. The hormone marker and PIT1 reductions observed in Lhx3(W227ter/W227ter) mice on a mixed background were also seen in the separate strains but in some cases were more severe in 129/Sv. To further characterize the molecular changes in diseased mice, we conducted a quantitative proteomic analysis of pituitary proteins. This showed significantly lower levels of PRL, pro-opiomelanocortin (ACTH), and α-glycoprotein subunit proteins in Lhx3(W227ter/W227ter) mice. Together, these data show that hormone deficiency disease is apparent in early prenatal stages in this CPHD model system. Furthermore, as is noted in human disease, genetic background significantly impacts the phenotypic outcome of these monogenic endocrine diseases.
联合垂体激素缺乏症 (CPHD) 会导致患者出现严重后果，包括身材矮小、发育迟缓和生殖缺陷。人们对其病因知之甚少，尤其是发育特征以及遗传背景对疾病进展的影响。CPHD 的动物模型为研究疾病机制以及为诊断和治疗方案提供信息提供了有价值的工具。在这里，我们检查了垂体发育过程中的激素产生情况，以及遗传背景对 Lhx3(W227ter/W227ter) 小鼠模型中表型严重程度的影响。Lhx3(W227ter/W227ter) 胚胎在产前发育过程中缺乏 ACTH、α-糖蛋白亚基、GH、PRL、TSHβ 和 LHβ。此外，突变小鼠的关键垂体转录激活因子-1 (PIT1) 显著减少。通过繁殖，Lhx3(W227ter/W227ter) 基因型被放置在 129/Sv 和 C57BL/6 背景下。有趣的是，遗传背景显著影响了存活率：虽然在 C57BL/6 中发现了预期频率的 Lhx3(W227ter/W227ter) 动物，但在 129/Sv 遗传环境中纯合动物无法存活。在混合背景下，Lhx3(W227ter/W227ter) 小鼠中观察到的激素标志物和 PIT1 减少也在单独的品系中出现，但在某些情况下，129/Sv 中的情况更为严重。为了进一步描述患病小鼠的分子变化，我们对垂体蛋白进行了定量蛋白质组学分析。结果表明，Lhx3(W227ter/W227ter) 小鼠的 PRL、前阿黑皮素原 (ACTH) 和 α-糖蛋白亚基蛋白水平显著降低。综上所述，这些数据表明，在这个 CPHD 模型系统中，激素缺乏疾病在早期产前阶段就很明显。此外，正如人类疾病中所注意到的，遗传背景显著影响这些单基因内分泌疾病的表型结果。
