Morphogenetic mechanisms regulating directed cell migration required to form the vertebrate posterior body

调节形成脊椎动物后体所需的定向细胞迁移的形态发生机制

• 批准号: 9403120
• 负责人: David Kimelman
• 金额: $ 33.13万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9403120
• 关键词: Adopted; Anterior; Biological Assay; Biological Models; Cell Proliferation; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Congenital Abnormality; Development; Down-Regulation; Embryo; Embryo Deaths; Failure; Gene Expression; Goals; Growth; Homeobox Genes; Individual; Lead; Measures; Mesoderm; Mesoderm Cell; Movement; Muscle; Neural tube; Neurons; Population; Process; Regulator Genes; Resolution; Somites; Spinal Cord; Stem cells; System; Testing; Time; Transgenic Organisms; Zebrafish; base; cell motility; cell type; cellular imaging; directional cell; epithelial to mesenchymal transition; high resolution imaging; in vivo; in vivo imaging; innovation; insight; loss of function; migration; mutant; novel; prevent; progenitor; relating to nervous system; rho; somitogenesis

PROJECT SUMMARY Much of the vertebrate embryonic body forms from a recently discovered neuromesodermal progenitor cell population located at the most posterior end of the early embryo, in a region called the Progenitor Zone (PZ). The PZ gradually releases mesodermal cells that populate the somites (primarily muscle) as well as the neural cells that form the spinal cord, until the complete anterior-posterior axis of the embryo has been established. While the mechanisms controlling the differentiation of the neuromesodermal cells are increasingly understood, how these cells regulate the completion of the epithelial to mesenchymal transition (EMT) and directional migration from the PZ into the body largely remains a mystery, yet this process is essential for the embryo to form its anterior-posterior axis correctly. Based on our analysis of a zebrafish mutant that specifically disrupts the migration of mesodermal cells from the PZ, we have identified a unique set of PZ-expressed Progenitor Cytoskeletal Regulatory Genes (PCRGs) that we propose must be down-regulated for cells to complete the EMT and migrate from the PZ into the presomitic mesoderm (PSM). Using a novel explant assay we recently developed that allows in vivo imaging of the migrating cells at very high resolution, in Aim 1 we will determine how the PCRGs are used to regulate the directional movement of cells into the PSM using a combination of gain and loss of function studies, as well as examining how the PCRGs control Rho activity. In Aim 2 we will determine how the posterior hox genes, which through unknown mechanisms control the orderly movement of cells from the PZ into the embryonic body, specifically regulate cell movements using our novel explant system to examine directional cell migration and protrusive activity of the hox-expressing cells. We will test the hypothesis that the hox genes act to sustain the expression of the PCRGs, and thereby regulate the timing of cell entry into the PSM. Collectively, these studies will examine the premise that the migration of cells from the PZ into the PSM is regulated by the action of the PCRGs and posterior hox genes, which acting together control the orderly anteriorward migration of newly differentiating mesodermal cells, thus allowing the vertebrate embryonic body to form with remarkable fidelity. With the ease of making transgenic lines that allow temporally controlled expression of the PCRGs and hox genes as well as CRISPR mutant lines, combined with our innovative explant system for high resolution imaging, zebrafish is an excellent system for understanding the mechanisms that control the early formation of the vertebrate body.

项目总结