The Function of the Mia3 Gene in Murine Placentation

Mia3 基因在小鼠胎盘形成中的功能

基本信息

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
项目类别：
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

项目摘要

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.

描述（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并分泌维持妊娠状态的激素母亲的。胎盘的结构很复杂，由子宫内的侵袭和锚定区域以及血管交换区域组成，所有这些区域都以滋养层细胞作为其主要结构和功能元素。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有关，包括自然流产、宫内生长受限和先兆子痫，所有这些通常都与胎盘血管系统受损有关。滋养层细胞起源于囊胚的上皮滋养外胚层细胞，并逐渐分化为具有特殊功能的多种亚型。一些调节滋养层特化的因素已开始被识别，但胎盘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。我们发现了一种参与小鼠胎盘形态发生的新基因，即黑色素瘤抑制活性 3 (Mia3)，它编码一种参与膜运输和高尔基体组织 (TANGO1) 的蛋白质。该基因在 ES 细胞中产生的基因陷阱突变（命名为 Xst199）导致纯合突变胚胎在妊娠第 10.5 天死亡，胎盘形态发生严重缺陷。该缺陷似乎至少起源于 E8.5，因为纯合突变体中的绒毛膜和外胎盘锥发育得不如杂合子和野生型同窝伴侣。培养的人类细胞中的 TANGO1 的功能是促进 COPII 包被的分泌囊泡装载特定的货物蛋白，因此我推测小鼠胚胎中 Tango1 的 Xst199 突变会干扰滋养层分化所需的蛋白质的分泌，从而导致胎盘功能障碍。在这项初步研究中，我建议进一步表征这种突变的表型和滋养层细胞中 Tango1 的正常功能，并确定这种新途径对调节滋养层细胞分化的重要性。公共卫生相关性：许多妊娠疾病，如先兆子痫、自然流产和宫内生长迟缓，都是由于胎盘形成缺陷造成的，可导致胎儿和母亲显着发病和死亡。为了了解其原因，我们需要更好地了解控制胎盘形成和功能的机制。 Mia3 基因的 Xst199 突变揭示了一条对于胎盘正常形成至关重要的新途径，因此进一步的工作对于充分了解该基因如何发挥作用以及它如何影响胎盘非常重要。