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: 8737012
• 负责人: Michel Bagnat
• 金额: $ 32.9万
• 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/8737012
• 关键词: Ablation; Affect; Aging; Amino Acid Transporter; Amino Acids; Amphibia; Anterior; Automobile Driving; Biogenesis; Biology; Birds; Cells; Chordata; Cilia; Congenital Scoliosis; 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; skeletal; trafficking; water channel

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：脊椎动物脊索在脊椎动物发育过程中起着关键的信号作用，在骨形成之前作为胚胎的静水骨架。脊椎动物脊索的中央是一个充满液体的大细胞器，即脊索液泡。这些充满液体的液泡在研究过的所有脊椎动物胚胎中都有描述，包括鱼类、两栖动物、鸟类和哺乳动物。在这些物种中，液泡持续存在于椎间盘髓核（IVD's）内，远远超过骨骼成熟，在那里它们保持渗透活性并继续发挥信号作用。令人惊讶的是，几乎没有