Motility and Guidance Signals Control Migration of Muscle Precursors

运动性和引导信号控制肌肉前体的迁移

基本信息

批准号：
10557028
负责人：
Jared Coffin Talbot
金额：
$ 25.95万
依托单位：
UNIVERSITY OF MAINE ORONO
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-04-05 至 2028-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10557028
关键词：
3-Dimensional Adult Agonist Antibodies Binding Biological Models Body Regions CXC Chemokines CXCR4 Receptors Cells Chemicals Chest Cues Data Destinations Development ESR2 gene Embryo Estrogen Receptor beta FDA approved Future Gene Expression Genes Genetic Genetic Epistasis Growth Human Impairment Knock-out Label Libraries Ligands Limb structure Location MET gene Malignant Neoplasms Mesenchymal Metastasis Induction Migration Assay Morphogenesis Movement Muscle Myoblasts Myomatous neoplasm Natural regeneration Neoplasm Metastasis Pathway interactions Pattern Pharmaceutical Preparations Phosphorylation Physiologic pulse Process Protein Dephosphorylation Proteins Shapes Signal Transduction Skeletal muscle structure of neck Somites Source Specific qualifier value Stream Stromal Cell-Derived Factor 1 System Testing Therapeutic Transgenic Organisms Zebrafish cell behavior cell growth regulation cell motility cell type cellular imaging chemokine cofactor epithelial to mesenchymal transition experimental study extracellular genetic approach homeodomain human disease improved in vivo inhibitor insight migration molecular drug target muscle regeneration mutant progenitor promoter receptor response screening small molecule libraries tissue regeneration tool transcription factor tumor tumor progression vertebrate embryos

项目摘要

Jared Talbot Project summary: Cell migrations are vital to generating a patterned musculature, but only a few of the cues that activate the cell’s motility are known and it remains unclear how muscle progenitors decide to move towards one destination versus another. Here, we will investigate the cues that activate muscle precursor cell motility (Aim 1) and guide the migrating cells (Aim 2) using zebrafish embryos as a model system. In vertebrate embryos, muscle precursor cell migration begins with an epithelial-to-mesenchymal transition (EMT); the cells are then actively guided from somites to new locations in the body, migrating as mesenchymal cell-streams. In mammalian embryos, these cell streams originate from several axial levels to generate over 100 muscles in many body regions. In zebrafish embryos, the homologous migrations are simpler, producing only four muscles: the two limb muscles, the sole neck muscle, and the chest muscle. Paired with other zebrafish strengths, this simplicity makes the zebrafish embryo an excellent model system for understanding muscle precursor cell migrations. We have developed transgenic and mutant lines that enable us to investigate muscle precursor migration in zebrafish embryos. Using these tools, we recently demonstrated that the transcription factors six1 and six4 (collectively termed “six1/4”) are essential for muscle precursor migration in zebrafish. In six1/4 mutants, the muscle precursors fail to undergo EMT and fail to activate the migration-promoting gene met, which encodes a metastasis-inducing receptor protein. Although the six1/4 mutants completely lack precursor migration, this process is only delayed in zebrafish met mutants, suggesting that six1/4 targets additional genes that stimulate motility. In Aim 1A, we will use an unbiased chemical screen to identify new molecules that stimulate muscle precursor motility and guidance. In Aim 1B, we investigate one pathway already suggested by this screen to influence EMT during this migration. In Aim 2, we will investigate how chemokine signals influence this migration. Muscle precursors are thought to be attracted by chemokine (Cxcl12) signaling, which is received by the receptor Cxcr4 and antagonized by the scavenging receptor Ackr3; we propose that the interplay of these two receptors imparts directionality to muscle precursor migration. Chemokine signaling will be altered using genetic mutants and chemical modulators. Cell movement will be analyzed using 3D cell tracking in transgenic embryos. Together these experiments will provide insights into the initiation and guidance of muscle precursor cells, with potential application in other migration-dependent processes like muscle regeneration and metastasis.

贾里德·塔尔伯特项目摘要：细胞迁移对于产生图案化的肌肉组织至关重要，但只有少数线索可以产生这种变化。激活细胞的运动性是已知的，但目前尚不清楚肌肉祖细胞如何决定在这里，我们将研究激活的线索。使用斑马鱼观察肌肉前体细胞运动（目标 1）并引导细胞迁移（目标 2）胚胎作为模型系统在脊椎动物胚胎中，肌肉前体细胞迁移开始于。然后，细胞从体节主动引导至上皮间质转化（EMT）；在哺乳动物胚胎中，作为间充质细胞流迁移到体内的新位置，这些细胞流起源于多个轴向水平，在许多部位产生 100 多块肌肉在斑马鱼胚胎中，同源迁移更简单，仅产生四个区域。肌肉：两肢肌肉、脚底颈部肌肉、胸部肌肉等。斑马鱼的优势，这种简单性使斑马鱼胚胎成为一个优秀的模型系统了解肌肉前体细胞迁移我们已经开发出转基因和突变体。使我们能够利用这些线来研究斑马鱼胚胎中的肌肉前体迁移。工具，我们最近证明了转录因子 Six1 和 Six4（统称为 “six1/4”）对于斑马鱼的肌肉前体迁移至关重要。前体细胞未能经历 EMT，也未能激活促进迁移的基因 met，这尽管 Six1/4 突变体完全缺乏编码转移诱导受体蛋白。前体迁移，这一过程仅在斑马鱼met突变体中延迟，这表明 Six1/4 的目标是刺激运动的其他基因。在目标 1A 中，我们将使用无偏的基因。化学筛选来识别刺激肌肉前体运动的新分子在目标 1B 中，我们研究了该屏幕已经建议的一种影响途径。在目标 2 中，我们将研究趋化因子信号如何影响这一迁移过程。肌肉前体细胞被认为是被趋化因子 (Cxcl12) 信号所吸引，它被受体 Cxcr4 接收并被清除受体 Ackr3 拮抗；提出这两种受体的相互作用赋予肌肉前体方向性趋化因子信号传导将通过基因突变和化学调节剂来改变。将使用转基因胚胎中的 3D 细胞追踪来分析细胞运动。实验将提供对肌肉前体细胞的启动和指导的见解，在其他依赖迁移的过程中的潜在应用，例如肌肉再生和转移。