Elucidation of a Brachyury-independent branch of the notochord gene regulatory network

脊索基因调控网络的 Brachyury 独立分支的阐明

• 批准号: 10528032
• 负责人: ANNA DI GREGORIO
• 金额: $ 8.03万
• 依托单位: NEW YORK UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-08-16 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10528032
• 关键词: Binding Sites; Body Patterning; Brachyury protein; Cell Nucleus; Cell Shape; Chordata; Chordoma; Complex; Comprehension; Congenital Abnormality; Defect; Development; Embryo; Embryonic Development; Embryonic Structures; Endoderm; Enhancers; Ensure; Event; Evolution; Extracellular Matrix; Gene Expression; Generations; Genes; Genetic; Genome; Goals; Heart; Heart Abnormalities; Human; Human Pathology; Impairment; Intervertebral disc structure; Knowledge; Light; Liver; Mediating; Molecular; Morphogenesis; Mus; Nature; Nervous system structure; Neuraxis; Nucleic Acid Regulatory Sequences; Ontology; Organ; Orthologous Gene; Pain; Pancreas; Paraxial Mesoderm; Pattern; Phenotype; Phylogenetic Analysis; Physiologic Ossification; Pregnancy; Primitive foregut structure; Public Health; Publishing; Research; Role; Shock; Skull Base Chordoma; Spinal Dysraphism; Structure; Tail; Transgenic Organisms; Vertebral column; Vertebrates; convergent extension; experimental study; gene regulatory network; insight; malformation; notochord; notochord development; novel; null mutation; postnatal; programs; rare cancer; skeletal; spine bone structure; transcription factor; vertebrate embryos

PROJECT SUMMARY/ABSTRACT During the early development of human and other vertebrate embryos, the notochord supports and instructs the formation of the body plan by patterning the central nervous system, paraxial mesoderm, endoderm and the numerous organs that they give rise to. Impairments in notochord formation cause birth defects and congenital skeletal malformations, while postnatally, alterations in the notochord remnants encased within the intervertebral discs are the main cause of discopathies and can give rise to rare tumors called chordomas. We are using the simple chordate Ciona to reconstruct the essential, evolutionarily conserved genetic toolkit of the notochord, with the ultimate goal of applying our findings to vertebrate development and human embryogenesis. We have shown that the notochord expression of a large number of vertebrate genes is conserved in Ciona and we have found that several Ciona notochord enhancers, the genetic switches that control notochord gene expression, share transcription factor binding sites with notochord regulatory regions that had been identified in vertebrates. Our published results provide ample evidence that the simple Ciona notochord expresses transcription factors (TFs) that are evolutionarily conserved in vertebrates, including humans, and are necessary for the development of this structure. The objective of this project is to study in detail one of these TFs, Ciona Lmx-like, and to clarify its role in notochord development. This objective will be achieved through the following experimental approaches: the elucidation of the role of Lmx-like in notochord morphogenesis (Aim 1); the identification of the notochord genes controlled by Lmx-like, and the functional characterization of a select group of them (Aim 2). Completion of these studies will shed light on an evolutionarily conserved TF, Lmx-like, which appears to act in parallel with Brachyury, the main regulator of notochord formation, and will provide a first insight into its role in notochord development. The expected results will shed light on the complex gene regulatory network that orchestrates notochord formation across chordates, and will provide a molecular blueprint for the interpretation of notochord-derived birth defects.

项目摘要/摘要 在人类和其他脊椎动物胚胎的早期发展过程中，脊索支持和 通过对中枢神经系统（近去中胚层）进行模仿，指导身体计划的形成， 内胚层及其产生的众多器官。脊索形成的障碍会导致出生 缺陷和先天性骨骼畸形，而在产后，诺修（Notochord）残留物发生了变化 被包裹在椎间盘中是疾病的主要原因，可以引起罕见的肿瘤 称为丘多马斯。我们正在使用简单的Chordate ciona重建必需的，进化 脊索的保守基因工具包，其最终目标是将我们的发现应用于脊椎动物 发育和人类胚胎发生。我们已经证明了大量的脊索表达 脊椎动物基因在Ciona中是保守的，我们发现几种ciona notochord增强剂，即 控制脊索基因表达，共享转录因子结合位点的遗传开关与脊索 在脊椎动物中鉴定出的监管区域。我们发表的结果提供了充分的证据表明 简单的ciona notochord表达了在进化中保守的转录因子（TFS） 脊椎动物，包括人类，对于这种结构的发展是必要的。 该项目的目的是详细研究这些TFS，类似于Ciona LMX，并阐明其作用 在脊索发展中。该目标将通过以下实验方法实现： 阐明LMX样在脊索形态发生中的作用（AIM 1）；脊索的识别 由LMX样控制的基因，以及其中一组的功能表征（AIM 2）。 这些研究的完成将揭示出一种进化保守的TF，LMX样，似乎 与诺修（Notochord）的主要监管机构Brachyury并行起作用，并将首先了解 它在脊索发展中的作用。预期的结果将揭示复杂的基因调节网络 这策划了跨弦的脊索形成，并将为该分子提供分子蓝图 解释诺修（Notochord）衍生的先天缺陷。