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

• 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
• 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

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.

Jared塔尔博特项目概要： 细胞迁移对于生成图案化的肌肉组织至关重要，但只有少数线索， 激活细胞的运动性是已知的，目前还不清楚肌肉祖细胞如何决定 走向一个目的地而不是另一个目的地在这里，我们将研究激活 肌肉前体细胞运动（Aim 1）和引导迁移细胞（Aim 2）使用斑马鱼 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 上皮细胞向间充质细胞转化（EMT）;然后细胞被积极引导从体节 转移到身体的新位置，作为间充质细胞流迁移。在哺乳动物胚胎中， 这些细胞流起源于几个轴向水平， 身体区域。在斑马鱼胚胎中，同源迁移更简单，只产生四个 肌肉：两个肢体肌肉，唯一的颈部肌肉和胸部肌肉。与其他配对 斑马鱼的优势，这种简单性使斑马鱼胚胎成为一个很好的模型系统， 了解肌肉前体细胞迁移。我们已经开发了转基因和突变体 这些线使我们能够研究斑马鱼胚胎中的肌肉前体迁移。使用这些 工具，我们最近证明，转录因子six 1和six 4（统称为 “six 1/4”）是斑马鱼肌肉前体迁移所必需的。在六个1/4突变体中， 前体不能进行EMT，不能激活促进迁移的基因met， 编码转移诱导受体蛋白。虽然六个1/4突变体完全缺乏 前体迁移，这一过程仅在斑马鱼Met突变体中延迟，这表明 six 1/4靶向刺激运动的额外基因。在目标1A中，我们将使用无偏 化学筛选，以确定刺激肌肉前体运动的新分子， 指导在目标1B中，我们研究了这个筛选已经提出的一种影响 在这次迁移中。在目标2中，我们将研究趋化因子信号如何影响这一点。 迁移肌肉前体被认为是由趋化因子（Cxcl 12）信号转导吸引的， 它被受体Cxcr 4接收并被清除受体Ackr 3拮抗;我们 我认为这两种感受器的相互作用赋予肌肉前体方向性 迁移趋化因子信号转导将使用遗传突变体和化学调节剂来改变。 将使用转基因胚胎中的3D细胞跟踪来分析细胞运动。综合这些 实验将提供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，如肌肉再生， 转移