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Temporal program for cell fate specification in the mouse embryo

小鼠胚胎细胞命运规范的时间程序

基本信息

批准号：
10443657
负责人：
Magdalena Zernicka-Goetz
金额：
$ 60.42万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10443657
关键词：
Actins Actomyosin Affect Apical Assisted Reproductive Technology Behavior Control Cell Cycle Cells Complex Cytoskeleton Data Defect Development Developmental Biology Dose Embryo Embryonic Development Ensure Event Experimental Models Fetus GATA3 gene Genetic Transcription Goals Human Imaging Techniques Inner Cell Mass Lead Light Link Mammals Mediating Medical Methods Modeling Morphogenesis Mus Myosin ATPase Nuclear Translocation Pharmacology Placenta Pregnancy loss Process Property Proteins Regenerative Medicine Reproduction Role Signal Transduction Testing Time Tissues To specify Totipotency Totipotent Up-Regulation Work base blastocyst cell fate specification cell type experimental study implantation insight mouse development natural Blastocyst Implantation novel optogenetics pluripotency polarized cell pregnancy failure pregnancy prevention preimplantation progenitor programs protein complex rho segregation self organization stem cell biology transcription factor zygote

项目摘要

SUMMARY. The first cell fate decision in mammals transforms a totipotent embryo comprising identical cells into two cell types: outer trophectoderm cells, which will give rise to the placenta, and inner pluripotent cells, which will give rise to the fetus. This decision depends on cell polarization. Although we understand how cell polarization connects to downstream signaling to specify the two cell types, the mechanisms that act earlier, to ensure cell polarization and its specific developmental timing, remain entirely unknown. To identify this mechanism, we first need to identify the upstream regulators, which have been elusive – until now. We recently found that two zygotically expressed transcription factors, Tfap2c and Tead4, together with Rho-mediated actomyosin activity, are essential and sufficient to trigger de novo cell polarization. These results provide us with an unprecedented opportunity to determine the mechanism that triggers the specific developmental timing of embryo polarization in early mammalian development. The objective of this proposal is to reveal the principles of self-organization that lead to de novo polarization and consequently the first cell fate specification in the key model mammalian embryo, the mouse embryo. Our central hypothesis is that zygotic transcription cooperates with the cytoskeleton to polarize cells and drive the first cell fate determination. We will test this hypothesis via the following Specific Aims: Aim 1: To determine what regulates timing of embryo polarization. We hypothesize that the timing of embryo polarization is controlled by Tfap2c and Tead4. We will alter the dose and developmental stage of Tfap2c and Tead4 expression and examine the effects on their downstream targets and the timing of embryo polarization. Aim 2: To determine how the apical domain becomes established. We hypothesize that Tfap2c and Tead4 regulate apical domain formation by modulating the actomyosin cytoskeleton, which in turn controls the conjugation of Par complex clusters. We will use advanced imaging techniques and pharmacological and optogenetic methods to determine the role of the actomyosin cytoskeleton in regulating apical domain formation and the dynamics of the Par complex during polarization. We will also examine how Tfap2c and Tead4 control the behavior of the actomyosin cytoskeleton and the organization of apical proteins into clusters to form the apical domain. Aim 3: To determine how altered timing of polarization affects embryo development. Embryo polarization always happens at the late 8-cell stage, just before the first cell fate decision, suggesting that the invariant timing of this polarization is critical for subsequent developmental progression. We will determine if accelerating the timing of embryo polarization by one cell cycle at the pre- implantation stage affects subsequent development, specifically cell fate and blastocyst formation before implantation and embryo morphogenesis post-implantation. We expect to discover the triggers and mechanisms that regulate the precise timing of cell polarization in the mouse embryo. Our work will likely have major medical relevance, as it will shed light on the causes of early developmental defects and pregnancy loss in humans.

总结。哺乳动物的第一个细胞命运决定将一个由相同细胞组成的全能胚胎转化为