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: 10650730
• 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/10650730
• 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; 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; cell behavior; cell motility; cell type; embryo cell; embryo tissue; experimental study; gastrulation; genetic manipulation; genetic risk factor; improved; in vivo; innovation; morphogens; neural; notochord; novel; optogenetics; pharmacologic; programs; prospective; receptor; response; transcriptomic profiling; 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.

项目概要 先天畸形或出生缺陷是美国 1 岁以下儿童死亡的主要原因 神经管缺陷（NTD）是最常见和最具破坏性的先天畸形之一， 是由于早期胚胎发育过程中神经管未能闭合造成的。 不仅需要成对的神经褶皱升起并融合在一起，而且还需要神经外胚层 （神经管的前体），充分变窄，使神经皱襞沿着中线相遇。 狭窄在原肠胚形成期间开始，并与同时发生的前后（AP）延伸相结合 神经外胚层是由细胞极化重排成更长更窄的阵列而产生的。 过程，适当地称为收敛和扩展（C＆E），是一个高度保守的形态发生 在塑造众多胚胎组织和建立动物身体计划方面发挥重要作用的机制。 神经管闭合和初级 AP 胚胎轴的延伸是由两个神经管的 C&E 驱动的 神经外胚层和下面的中胚层，每一个都表现出一套独特的细胞行为 然而，人们对组织特性如何协调仍知之甚少。 具有组织特异性细胞行为程序。 在这里，我们解决了斑马鱼模型中轴延伸的组织特异性形态发生 我们最近报道 TGF-β 家族形态发生素 Nodal 不仅是脊椎动物胚胎所必需的。 斑马鱼的 C&E 原肠胚形成运动，但也足以促进其他细胞的这些行为 幼稚的斑马鱼胚胎外植体通过改变节点信号激活的方法，我们可以驱动组织- 重要的是，这使我们能够对这些外植体中的神经外胚层或中胚层进行特异性 C&E。 解开各个组织层的形态发生并区分控制细胞身份的机制 每种 C&E 模式都与特定的发育高峰相关。 节点活动和转录谱，引导我们捕获节点活动的时间模式 通过不同的下游分子程序定义组织特异性形态发生。 目标 1 中提出的实验将测试如何通过光遗传学方法精确操纵节点活动 在目标 2 和 3 中，时间信号动力学的变化控制体内和体外的组织特异性 C&E。 将定义每个节点依赖性基因表达程序所需的特定组件 和/或分别足以用于中胚层和神经外胚层的组织特异性 C&E。 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 在轴延伸中具有新作用的基因，从而增进对神经管的基本理解 关闭对于改进 NTD 的诊断、预防和治疗策略至关重要。