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Mechanistic roles of the basement membrane mechanics in cellular morphodynamics and tissue patterning of the pre-gastrulating embryo

基底膜力学在原肠胚形成前细胞形态动力学和组织模式中的作用

基本信息

批准号：
10617195
负责人：
Dong-Yuan Chen
金额：
$ 2.53万
依托单位：
CALIFORNIA INSTITUTE OF TECHNOLOGY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10617195
关键词：
3-Dimensional Acute Address Affect Animals Anterior Architecture Basement membrane Biological Biological Process Biology California Cells Cellular biology Collaborations Complex Defect Development Developmental Biology Diffusion Embryo Embryonic Development Endoderm Endoderm Cell Environment Epiblast Epithelium Event Fellowship Fertilization Fluorescent in Situ Hybridization Fostering Foundations Future Gene Expression Genes Genetic Goals Human Image Image Analysis In Situ In Situ Hybridization Infertility Knowledge Learning Malignant Neoplasms Mammals Maps Mechanics Mesenchymal Modeling Molecular Morphogenesis Mus Neoplasm Metastasis Organ Pathologic Processes Pattern Pattern Formation Persons Play Pregnancy Prevention Principal Investigator Process Property Reaction Research Role Route Signal Transduction Specific qualifier value Structure Techniques Technology Testing Tissues Training Visceral Work blastomere structure cancer diagnosis cancer prevention career cell behavior cell fate specification conditional knockout differential expression early pregnancy loss embryo cell embryo culture embryo tissue experimental study extracellular gastrulation genetic manipulation image processing imaging approach implantation insight interdisciplinary collaboration mammalian embryology mathematical model migration mortality multi-scale modeling natural Blastocyst Implantation novel strategies preservation quantitative imaging skills stem cells superresolution microscopy tool transcriptome transcriptomics

项目摘要

Project Summary/Abstract Establishing proper tissue-level architecture and patterning during early embryogenesis is crucial for a successful pregnancy. A high rate of mortality seen in human embryos during the first 2-3 weeks post-fertilization is a major cause of early pregnancy loss, yet the essential cellular, molecular, and mechanical changes remain poorly defined. During early post-implantation mammalian embryogenesis, an extra-embryonic epithelial layer, the visceral endoderm, plays an essential role in the symmetry-breaking event that specifies the anterior- posterior patterning of the epiblast. Specifically, a subset of the visceral endoderm cells, the anterior visceral endoderm, migrates toward one end of the future anterior-posterior axis to pattern the epiblast. Recent work from our lab reveals that the embryonic basement membrane plays an essential role in symmetry breaking and morphogenesis that sets the stage for gastrulation. However, how the extracellular mechanics modulates the collective cellular dynamics and instructs cell identities for pattern formation remains not known. Here we propose to determine how the embryonic basement membrane coordinates the collective cell behaviors and facilitates anterior-posterior specification for pattern formation. First, we will comprehensively map the cell behaviors of the entire visceral endoderm with imaging approaches and define the role of the basement membrane in anterior visceral endoderm migration through genetic perturbations in stem cell-derived embryo- like structures as well as in the natural embryos. Next, we will map the basement membrane mechanics and apply a single-cell transcriptomics approach to generate in situ cell fate maps of the pre-gastrulating embryos. We will functionally test how the basement membrane mechanics regulate cell identities by correlating the gene expression profiles with basement membrane architecture and validate the findings with basement membrane- perturbed embryos. Finally, we will implement multi-scale mathematical models that integrate cell identities and cell dynamics with the basement membrane mechanics to uncover mechanisms of pattern formation. Overall, these experiments will unveil functional roles of the extraembryonic environment in defining the cell identities of the pre-gastrulation embryos. These findings will inform subsequent studies in my future goals on the conserved roles of the basement membrane and the extraembryonic tissues in topologically distinct embryos seen in human. Training during my fellowship period will expand my skillsets toward studying the more complex biology of mammals and broaden my knowledge on new aspects of developmental biology. The research environment at California Institute of Technology will further foster interdisciplinary collaborations that allow the development of novel approaches to investigate early mammalian embryogenesis.

项目总结/文摘