The Function of the Mia3 Gene in Murine Placentation

Mia3 基因在小鼠胎盘形成中的功能

• 批准号: 8191466
• 负责人: Ann E Sutherland
• 金额: $ 7.7万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8191466
• 关键词: Affect; Apoptosis; Binding; Biological Models; Blood Vessels; COPII-Coated Vesicles; Cell Culture Techniques; Cell Differentiation process; Cell Line; Cell physiology; Cells; Cessation of life; Chorion; Complex; Defect; Development; Diffusion; Disease; Elements; Embryo; Embryonic Development; Endocrine; Endoplasmic Reticulum; Environment; Epithelial; Failure; Fetal Death; Fetal Growth Retardation; Fetus; Functional disorder; Gases; Gene Expression; Gene Mutation; Genes; Golgi Apparatus; Hormones; Human; In Situ Hybridization; Invaded; Lead; Molecular; Morbidity - disease rate; Morphogenesis; Mothers; Mus; Mutate; Mutation; Nutrient; Organ; Oxygen; Partner in relationship; Pathway interactions; Pattern; Phenotype; Pilot Projects; Placenta; Placentation; Pre-Eclampsia; Pregnancy; Process; Protein Secretion; Proteins; Regulation; Retinal Cone; Role; Secretory Vesicles; Spontaneous abortion; Stem cells; Structure; Transmembrane Transport; Uterus; Western Blotting; Work; blastocyst; embryonic stem cell; fetal; insight; melanoma; mortality; mutant; novel; pregnancy disorder; pregnant; receptor; research study; trophoblast; wasting

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.

描述（由申请人提供）：胎盘是哺乳动物胚胎发生的关键器官，可在母亲和胎儿之间提供有效的营养，气体和废物交换，并为胎儿和分泌孕妇的孕激素创造一种免疫学特权的环境。胎盘的结构很复杂，由子宫内的入侵和锚定区域以及血管交换区域组成，所有这些区域均以滋养细胞为主要的结构和功能元素。滋养细胞细胞正确侵袭和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有关，包括自发流产，宫内生长限制和先兆子痫，所有这些通常都与受损的胎盘脉管系统有关。滋养细胞细胞来自胚泡的上皮滋养剂细胞，并逐渐区分为具有专门功能的多种亚型。调节滋养细胞专业化的一些因素已经开始鉴定，但是胎盘的分化和形态发生的细胞和分子机制在很大程度上尚不清楚。我们已经确定了一个与小鼠黑色素瘤抑制活性3（MIA3）中胎盘形态发生有关的新基因，该基因编码涉及膜转运和高尔基组织（Tango1）的蛋白质。该基因在ES细胞中产生的基因陷阱突变，指定为XST199，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。缺陷似乎至少起源于E8.5，因为在纯合突变体中的绒毛膜和外部锥体比在杂合和野生型垃圾伴侣中发育良好。培养的人类细胞中的Tango1功能促进具有特定的货物蛋白的Copii涂层分泌囊泡的负载，因此我假设小鼠胚胎中Tango1的XST199突变干扰了特异性分泌的蛋白质，这些蛋白质是特异性的，这些蛋白质是特异性的，这些蛋白质特异性地分泌了toplast的分化，从而导致胎盘功能障碍。在这项试验研究中，我建议进一步表征该突变的表型和探戈1在滋养细胞细胞中的正常功能，并确定这种新型途径对调节滋养细胞分化的重要性。 公共卫生相关性：许多怀孕的疾病，例如先兆子痫，自发性流产和宫内生长迟缓是由于胎盘形成的缺陷所致，并且可能导致胎儿和母亲的显着发病率和死亡率。要了解它们的原因，我们需要更好地理解管理胎盘形成和功能的机制。 MIA3基因的XST199突变发现了一种新的途径，这对于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起作用以及它如何影响胎盘很重要。