Uncovering mechanisms controlling notochord vacuole and spine morphogenesis

揭示控制脊索液泡和脊柱形态发生的机制

基本信息

批准号：
8613133
负责人：
Michel Bagnat
金额：
$ 32.91万
依托单位：
DUKE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-17 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8613133
关键词：
Ablation Affect Aging Amino Acid Transporter Amino Acids Amphibia Anterior Automobile Driving Biogenesis Biology Birds Cells Chordata Cilia Defect Development Economic Inflation Embryo Embryonic Development Epithelial Etiology Event Fishes Goals Hydrostatic Pressure Image Intervertebral disc structure Invaded Laboratories Life Liquid substance Lysosomes Maintenance Mammals Membrane Membrane Proteins Microtubules Modeling Molecular Morphogenesis Organelles Osteoblasts Osteogenesis Patients Play Process Proton-Translocating ATPases Recording of previous events Role Shapes Signal Transduction Skeleton Sorting - Cell Movement Structure System Testing Transgenic Organisms Vacuole Vertebral Bone Vertebral column Vertebrates Water Water Movements Work Zebrafish base kinetosome notochord novel nucleus pulposus pressure public health relevance scaffold scoliosis skeletal trafficking water channel

项目摘要

Abstract In vertebrates the notochord plays critical signaling roles during vertebrate development and acts as a hydrostatic skeleton for the embryo before bone formation. At the center of the vertebrate notochord is a large fluid-filled organelle, the notochord vacuole. These fluid-filled vacuoles have been described in every vertebrate embryo studied including fish, amphibians, birds, and mammals. In these species the vacuoles persist within the nucleus pulposus of the intervertebral discs (IVD's), well beyond skeletal maturity, where they remain osmotically active and continue to play signaling roles. Surprisingly, little was known about the molecular mechanisms involved in notochord vacuole biogenesis and maintenance. Recent work in zebrafish from our laboratory has shown that notochord vacuoles are specialized lysosome-related organelles. We established that notochord vacuoles are required for antero-posterior (AP) axis elongation during embryonic development and identified a novel role for this fluid filled organelle in spine morphogenesis. We found that loss of vacuole integrity leads to kinks in the spine axis similar to those observed in congenital scoliosis (CS) patients. Thus, the vertebrate notochord plays a critical role in spine morphogenesis. Our goal here is to use the zebrafish system to uncover molecular mechanisms controlling notochord vacuole formation and maintenance and to characterize the role these vacuoles play in spine morphogenesis. These studies will help better understand the etiology of congenital scoliosis and other poorly understood spine defects as well as IVD processes associated with aging.

抽象的在脊椎动物中，脊索在脊椎动物发育过程中起关键的信号传导作用，并充当骨形成前的胚胎静水骨架。在脊椎动物脊索的中心很大充满流体的细胞器，脊索液泡。这些充满流体的液泡已经描述了脊椎动物的胚胎研究包括鱼，两栖动物，鸟类和哺乳动物。在这些物种中，液泡持续存在椎间盘（IVD）的细胞核孔，远远超出了骨骼成熟度保持渗透活跃并继续扮演信号角色。令人惊讶的是，对参与脊索液泡生物发生和维持的分子机制。斑马鱼的最新工作从我们的实验室中表明，诺修（Notochord Vacuoles）是专门的溶酶体相关细胞器。我们确定胚胎期间的前后轴（AP）轴伸长需要Notochord液泡发育并确定了这种液体填充细胞器在脊柱形态发生中的新作用。我们发现液泡完整性的丧失会导致脊柱轴的扭结，类似于先天性脊柱侧弯（CS）的链轴。患者。因此，脊椎动物脊索在脊柱形态发生中起着至关重要的作用。我们的目标是使用斑马鱼系统，以发现控制诺修液液的分子机制和维护并表征这些液泡在脊柱形态发生中所起的作用。这些研究将有助于更好地了解先天性脊柱侧弯的病因和其他知识不足的脊柱缺陷以及IVD 与衰老相关的过程。