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

• 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
• 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

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.

摘要 在脊椎动物中，脊索在脊椎动物发育过程中起着关键的信号作用， 骨骼形成前胚胎的流体静力学骨骼。在脊椎动物脊索的中心是一个大的 充满液体的细胞器，脊索液泡。这些充满液体的空泡在每一个 研究脊椎动物胚胎，包括鱼、两栖动物、鸟类和哺乳动物。在这些物种中， 持续存在于椎间盘的髓核（IVD）中，远远超过骨骼成熟期， 继续发挥积极作用，继续发挥信号作用。令人惊讶的是， 参与脊索液泡生物发生和维持的分子机制。斑马鱼的最新研究 已经表明脊索空泡是专门的溶酶体相关细胞器。我们 建立了脊索空泡是胚胎期前后轴伸长所必需的 发展，并确定了一个新的作用，这种流体充满细胞器在脊柱形态发生。我们发现 空泡完整性的丧失导致脊柱轴扭结，类似于先天性脊柱侧凸（CS）中观察到的扭结 患者因此，脊椎动物脊索在脊柱形态发生中起着关键作用。我们的目标是利用 斑马鱼系统，以揭示控制脊索液泡形成的分子机制， 维持和表征这些空泡在脊柱形态发生中的作用。这些研究将有助于 更好地了解先天性脊柱侧凸和其他尚不清楚的脊柱缺陷以及IVD的病因 与衰老相关的过程。