The Function of the Mia3 Gene in Murine Placentation

描述（由申请人提供）：胎盘是哺乳动物胚胎发生的关键器官，在母体和胎儿之间提供有效的营养、气体和废物交换，并为胎儿创造免疫特权环境，分泌维持母体妊娠状态的激素。胎盘的结构很复杂，包括子宫内的侵入和锚定区域以及血管交换区域，所有这些区域都具有滋养层细胞作为其主要结构和功能元件。滋养层细胞侵入并正确形成胎盘的能力对于成功发育至关重要;胎盘功能障碍与许多妊娠疾病相关，包括自然流产、宫内生长受限和先兆子痫，所有这些通常与胎盘血管受损相关。滋养层细胞起源于胚泡的上皮滋养外胚层细胞，并逐渐分化为具有专门功能的各种亚型。一些调节滋养层特化的因子已开始被确定，但胎盘分化和形态发生的细胞和分子机制在很大程度上是未知的。我们已经确定了一个新的基因参与胎盘形态发生的小鼠，黑色素瘤抑制活性3（Mia 3），它编码的蛋白质参与膜运输和高尔基体组织（TANGO 1）。在胚胎干细胞中产生的该基因的基因陷阱突变，命名为Xst 199，导致妊娠第10.5天纯合突变胚胎死亡，胎盘形态发生严重缺陷。该缺陷似乎起源于至少早在E8.5，作为绒毛膜和外胎盘锥是不太发达的纯合突变体比杂合和野生型同窝仔。TANGO 1在培养的人类细胞中的功能是促进COPII包被的分泌囊泡与特定货物蛋白的装载，因此我假设TANGO 1在小鼠胚胎中的Xst 199突变干扰滋养层分化特异性所需的蛋白质的分泌，导致胎盘功能障碍。在这项初步研究中，我建议进一步表征这种突变的表型和Tango 1在滋养层细胞中的正常功能，并确定这种新途径对滋养层细胞分化调节的重要性。 公共卫生相关性：许多妊娠期疾病，如先兆子痫、自然流产和宫内发育迟缓，都是由于胎盘形成缺陷所致，可导致胎儿和母亲的显著发病率和死亡率。为了了解其原因，我们需要更好地了解胎盘形成和功能的机制。Mia 3基因的Xst 199突变揭示了一种新的途径，这对胎盘的正确形成至关重要，因此进一步的工作对于充分了解该基因的功能以及它如何影响胎盘形成非常重要。

DESCRIPTION (provided by applicant): The placenta is a critical organ of mammalian embryogenesis, providing efficient nutrient, gas and waste exchange between the mother and fetus, as well as creating an immunologically privileged environment for the fetus and secreting hormones that maintain the pregnant state of the mother. The structure of the placenta is complex, consisting of regions of invasion and anchorage within the uterus as well as a region of vascular exchange, all of which have trophoblast cells as their primary structural and functional elements. The ability of the trophoblast cells to invade and form the placenta properly is crucial for successful development; placental dysfunction is associated with many disorders of pregnancy, including spontaneous abortions, intrauterine growth restriction, and preeclampsia, all of which are commonly associated with compromised placental vasculature. Trophoblast cells arise from the epithelial trophectoderm cells of the blastocyst and progressively differentiate into a variety of subtypes with specialized functions. Some of the factors regulating trophoblast specialization have begun to be identified, but the cellular and molecular mechanisms underlying differentiation and morphogenesis of the placenta are largely unknown. We have identified a novel gene involved in placental morphogenesis in the mouse, melanoma inhibitory activity 3 (Mia3), which encodes a protein involved in membrane transport and Golgi organization (TANGO1). A gene-trap mutation of this gene generated in ES cells, designated Xst199, leads to death of homozygous mutant embryos at day 10.5 of gestation, with severe defects in placental morphogenesis. The defect appears to originate at least as early as E8.5, as the chorion and ectoplacental cone are less well developed in the homozygous mutants than in heterozygous and wild type litter mates. TANGO1 in cultured human cells functions to facilitate loading of COPII coated secretory vesicles with specific cargo proteins, thus I hypothesize that the Xst199 mutation of Tango1 in mouse embryos interferes with secretion of proteins specifically required for trophoblast differentiation, leading to placental dysfunction. In this pilot study I propose to further characterize the phenotype of this mutation and the normal function of Tango1 in trophoblast cells, and determine the importance of this novel pathway to the regulation of trophoblast cell differentiation. PUBLIC HEALTH RELEVANCE: Many of the diseases of pregnancy such as preeclampsia, spontaneous abortion, and intrauterine growth retardation are due to defects in the formation of the placenta, and can lead to significant morbidity and mortality to both fetus and mother. To understand their causes, we need to better understand the mechanisms governing the formation and function of the placenta. The Xst199 mutation of the Mia3 gene has uncovered a novel pathway that is critical for the proper formation of the placenta, and thus further work is important to fully understand how this gene is functioning, and how it affects placentation.