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: 10684757
• 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/10684757
• 关键词: Acceleration; Binding Sites; Body Patterning; Brachyury protein; Cell Nucleus; Cell Shape; Central Nervous System; 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; Lateral; Liver; Mediating; Molecular; Morphogenesis; Mus; Nature; Nervous System; 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; Visualization; absorption; 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育过程中，脊索支持和 通过对中枢神经系统、旁轴中胚层、 内胚层及其产生的众多器官。脊索形成障碍会导致出生 畸形和先天性骨骼畸形，而出生后脊索残留物的改变 盘内包裹是导致椎间盘病变的主要原因，并可导致罕见的肿瘤。 称为脊索瘤。我们正在使用简单的弦状Ciona来重建本质的，进化的 保存脊索的遗传工具包，最终目标是将我们的发现应用于脊椎动物 发育和人类胚胎发育。我们已经证明了大量的脊弦表达 脊椎动物的基因在Ciona中是保守的，我们发现几种Ciona脊索增强剂， 控制脊索基因表达的遗传开关，与脊索共享转录因子结合位点 已经在脊椎动物中发现的调控区域。我们公布的结果提供了充分的证据 简单的Ciona脊索表达转录因子(TF)，这些转录因子在进化中是保守的 脊椎动物，包括人类，是这种结构发展所必需的。 这个项目的目标是详细研究其中的一个，Ciona LMX-like，并阐明它的作用 在脊索发育中。这一目标将通过以下试验方法来实现： LMX样蛋白在脊索形态发生中的作用(目标1)；脊索的鉴定 由类LMX控制的基因，以及其中选定的一组基因的功能特征(目标2)。 这些研究的完成将揭示一种进化上保守的Tf，LMX样蛋白，它出现了 与脊索形成的主要调节者短索并行行动，并将提供对 它在脊索发育中的作用。预期的结果将揭示复杂的基因调控网络。 这将协调脊索动物的脊索形成，并将为 脊索来源的出生缺陷的解释。