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Revealing how cytoskeletal dynamics form the early mammalian embryo

揭示细胞骨架动力学如何形成早期哺乳动物胚胎

基本信息

批准号：
10117399
负责人：
Nicolas Daniel Plachta
金额：
$ 51.4万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10117399
关键词：
Actins Address Apical Automobile Driving Cell Communication Cell Differentiation process Cell Lineage Cell Nucleus Cell Polarity Cell Separation Cell division Cells Cytokeratin filaments Data Development Elements Embryo Event F-Actin Fetus Filament Future Goals Image Implant Inherited Inner Cell Mass Intermediate Filaments Interphase Keratin Length Mammalian Cell Measurement Mechanics Microtubules Mitosis Modeling Molecular Molecular Chaperones Movement Mus Nonmammalian Embryo Nuclear Organism PARD6A gene Pattern Placenta Pregnancy Process Proteins Role Specific qualifier value Testing Time To specify Uterus Work base biophysical properties biophysical techniques blastocyst cell cortex cell type daughter cell embryo cell embryo stage 2 genetic risk factor imaging approach in vivo mechanical force molecular asymmetry molecular dynamics mouse development overexpression preimplantation premature scaffold segregation transcription factor

项目摘要

SUMMARY Revealing the key events that specify the first differentiated cell lineages during mammalian development is key to understand how the early embryo is organized to implant in the uterus and establish a pregnancy. The first mammalian cell lineages comprise the pluripotent inner cell mass (ICM) that will form the fetus, and the outer trophectoderm that will form the placenta. Yet, the mechanisms explaining how these lineages differentiate are unclear. In many non-mammalian embryos, asymmetrically inherited cell-fate determinants specify lineage fate, yet similar mechanisms are thought to be absent during early mammalian development. We have established live-imaging approaches to study cell and molecular dynamics during early mouse development. Recently, we identified a new role for intermediate filaments assembled by keratins in lineage specification. Our studies reveal that keratin filaments are asymmetrically inherited precisely during the cell divisions that physically segregate the future ICM and trophectoderm. Moreover, the inheritance of these filaments by the outer daughter cells helps to specify their trophectoderm identity and promote their maturation. Thus, our main hypothesis is that keratin filaments function as a new form of asymmetrically inherited factor specifying the first trophectoderm cells during development. To test this, we will reveal the mechanisms by which keratins become asymmetrically inherited (Aim 1) and can bias cell fate (Aim 2). We will first test how interactions with proteins present at the apical cell cortex, and the dynamics of the filaments inside the cell, control their asymmetric inheritance by outer cells during cell division. We will then determine how keratins can regulate key aspects of cell mechanics and polarity to control the distribution of the key transcription factors that specify trophectoderm fate. In summary, in this proposal we will address a fundamental open question about the specification of the first differentiated cell lineages during mammalian development, and unveil some of the first functions of keratin intermediated filaments during early mammalian development, which unlike those of other cytoskeletal elements like microtubules and actin, remain largely unknown.

概括揭示哺乳动物发育过程中第一个分化细胞谱系的关键事件是关键了解早期胚胎如何组织植入子宫并建立妊娠。第一个哺乳动物细胞谱系包括将形成胎儿的多能内细胞团（ICM）和外细胞团将形成胎盘的滋养外胚层。然而，解释这些谱系如何分化的机制是不清楚。在许多非哺乳动物胚胎中，不对称遗传的细胞命运决定因素指定了谱系命运，然而，人们认为在早期哺乳动物发育过程中不存在类似的机制。我们已经建立了实时成像方法来研究早期小鼠的细胞和分子动力学发展。最近，我们发现了角蛋白组装的中间丝在谱系中的新作用规格。我们的研究表明，角蛋白丝在细胞内精确地不对称遗传在物理上将未来的 ICM 和滋养外胚层分开。而且，这些传承外部子细胞的细丝有助于确定其滋养外胚层的身份并促进其成熟。因此，我们的主要假设是角蛋白丝作为一种新形式的不对称遗传因子发挥作用指定发育过程中的第一个滋养外胚层细胞。为了测试这一点，我们将揭示其机制角蛋白变得不对称遗传（目标 1）并可能使细胞命运发生偏差（目标 2）。我们将首先测试与顶端细胞皮质中蛋白质的相互作用，以及细丝的动力学在细胞内部，在细胞分裂过程中通过外部细胞控制其不对称遗传。然后我们将确定如何角蛋白可以调节细胞力学和极性的关键方面，以控制关键转录的分布指定滋养外胚层命运的因素。总之，在这个提案中，我们将解决一个关于第一个规范的基本开放问题在哺乳动物发育过程中分化的细胞谱系，并揭示了角蛋白的一些最初功能哺乳动物早期发育过程中的中间丝，与其他细胞骨架元件不同像微管和肌动蛋白一样，仍然很大程度上未知。