Molecular drivers of tissue-specific morphogenetic programs

组织特异性形态发生程序的分子驱动因素

• 批准号: 10440153
• 负责人: Margot L.K. Williams
• 金额: $ 44.35万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-06-22 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10440153
• 关键词: Address; Age; American; Animals; Automobile Driving; Brain; Cause of Death; Cells; Child; Congenital Abnormality; Coupled; Defect; Development; Developmental Process; Diagnosis; Embryo; Embryonic Development; Ephrins; Exhibits; Extracellular Matrix; Failure; Family; Future; Gene Expression; Gene Expression Profile; Genes; Germ Layers; Head; Heart; Individual; Instruction; Intuition; Ligands; Link; Mesoderm; Methods; Modeling; Molecular; Morphogenesis; Movement; Neural Fold; Neural Tube Closure; Neural Tube Defects; Neural Tube Development; Neural tube; Neuroectoderm; Nodal; Organ; Pattern; Pharmacology; Prevention strategy; Procedures; Process; Reporting; Rod; Role; Shapes; Signal Transduction; Signaling Molecule; Specific qualifier value; Spinal Cord; Tail; Testing; Tissue-Specific Gene Expression; Tissues; Tube; Variant; Zebrafish; blastomere structure; cell behavior; cell motility; cell type; embryo tissue; experimental study; gastrulation; genetic manipulation; genetic risk factor; improved; in vivo; innovation; morphogens; notochord; novel; optogenetics; programs; prospective; receptor; relating to nervous system; response; transcriptomics; treatment strategy; vertebrate embryos

Project summary Congenital malformations, or birth defects, are the leading cause of death of American children under the age of nine. Neural tube defects (NTDs) are among the most common and devastating congenital malformations, and result from a failure of the neural tube to close during early embryonic development. Neural tube closure requires not only that the paired neural folds raise and fuse together, but also that the neuroectoderm (precursor to the neural tube), narrows sufficiently for the neural folds to meet along the midline. This critical narrowing begins during gastrulation and is coupled to a concurrent anteroposterior (AP) extension of the neuroectoderm that results from the polarized rearrangement of cells into a longer and narrower array. This process, appropriately termed convergence & extension (C&E), is a highly conserved morphogenetic mechanism with essential roles in shaping numerous embryonic tissues and establishing the animal body plan. Neural tube closure and extension of the primary AP embryonic axis are driven by C&E of both the neuroectoderm and the underlying mesoderm, each of which exhibits a distinct suite of cell behaviors and contributes actively to axis extension. It remains poorly understood, however, how tissue identity is coordinated with tissue-specific cell behavior programs. Here, we address the tissue-specific morphogenesis underlying axis extension in zebrafish, a model vertebrate embryo. We recently reported that the TGF- family morphogen Nodal is not only necessary for C&E gastrulation movements in zebrafish, but also sufficient to promote these cell behaviors in otherwise naïve zebrafish embryonic explants. By varying the method of Nodal signaling activation, we can drive tissue- specific C&E of either the neuroectoderm or mesoderm within these explants. Importantly, this allows us to uncouple morphogenesis of individual tissue layers and distinguish the mechanisms that control cell identity from those that control cell movement. Each mode of C&E is associated with a specific developmental peak of Nodal activity and transcriptional profile, leading us to hypothesize that temporal patterns of Nodal activity define tissue-specific morphogenesis via distinct downstream molecular programs. Using cutting-edge optogenetic approaches to precisely manipulate Nodal activity, experiments proposed in Aim 1 will test how variations in temporal signaling dynamics control tissue-specific C&E both in and ex vivo. In Aims 2 and 3, we will define the specific components of each Nodal-dependent gene expression program that are necessary and/or sufficient for tissue-specific C&E of the mesoderm and neuroectoderm, respectively. This proposal leverages the unique advantages of our innovative explant model and optogenetic approaches to identify genes with novel roles in axis extension, thereby advancing a fundamental understanding of neural tube closure essential for improved diagnosis, prevention, and treatment strategies for NTDs.

项目摘要 先天性畸形或先天缺陷是美国儿童以下儿童死亡的主要原因 九。神经管缺陷（NTD）是最常见和毁灭性的先天性畸形之一， 并导致神经管在早期胚胎发育过程中无法关闭。神经管闭合 不仅需要配对的神经福音升高并融合在一起，还需要神经外胚层 （神经管道的前体），狭窄，使神经福音沿中线相遇。这个批评 缩小开始时开始时，并与并发的前后延伸（AP）耦合 神经外胚层由细胞的极化重排而导致更长且较窄的阵列产生。这 过程，适当称为收敛与扩展（C＆E），是一种高度保守的形态学 在塑造众多胚胎组织和建立动物体计划中具有重要作用的机制。 神经管闭合和主要AP胚胎轴的延伸均由两者的C＆E驱动 神经外胚层和潜在的中胚层，每种表现出独特的细胞行为和 会积极促进轴扩展。然而，它仍然很了解组织身份如何协调 与组织特异性细胞行为程序。 在这里，我们解决了斑马鱼中的组织特异性形态发生的基础轴延伸，一个模型 脊椎动物胚胎。我们最近报告说，TGF-家族形态淋巴结不仅需要 斑马鱼中的C＆E胃胃运动，但也足以促进这些细胞行为 天真的斑马鱼胚胎外植体。通过改变淋巴结信号激活的方法，我们可以驱动组织 - 这些外植体中神经外胚层或中胚层的特定C＆E。重要的是，这使我们能够 解开单个组织层的形态发生，并区分控制细胞身份的机制 来自控制细胞运动的人。 C＆E的每种模式都与特定的发展峰有关 淋巴结活性和转录曲线，导致我们假设淋巴结活动的临时模式 通过不同的下游分子程序来定义组织特异性的形态发生。使用尖端 精确操纵淋巴结活性的光遗传学方法，AIM 1中提出的实验将测试如何测试 临时信号传导动力学的变化控制组织特异性的C＆E在体内和离体中。在目标2和3中，我们 将定义必要的每个淋巴结基因表达程序的特定组件 和/或适用于中胚层和神经外胚层的组织特异性C＆E。这个建议 利用我们创新的外植体模型和光遗传学方法的独特优势来识别 在轴扩展中具有新作用的基因，从而提高了对神经管的基本理解 闭合对于改善NTD的诊断，预防和治疗策略至关重要。