Segmentation Defects in Vertebrate Paraxial Mesoderm

脊椎动物近轴中胚层的分割缺陷

• 批准号: 7255916
• 负责人: ROBERT K HO
• 金额: $ 9.67万
• 依托单位: UNIVERSITY OF CHICAGO
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7255916
• 关键词: Alagille syndrome; body regions; cell differentiation; cell migration; cell type; confocal scanning microscopy; cytogenetics; developmental genetics; embryo /fetus tissue /cell culture; embryogenesis; gene expression; gene mutation; green fluorescent proteins; histogenesis; immunocytochemistry; mesoderm; messenger RNA; single cell analysis; skeletal disorder; vertebrate embryology; video microscopy; zebrafish

Recently, mutations in genes for the Notch ligands Jagged1 and Delta-like3 were shown to be responsible for two human malsegmentation disorders, Alagille syndrome and Spondylocostal dysostosis. A new perspective towards an understanding of these diseases is offered by the discovery of genes within the Notch pathway which exhibit dynamic, oscillating expression patterns in the tissues that form the skeleton and muscles of the adult body. The formation of reiterated segments is a common theme in many organisms including humans. Further knowledge of how segmentation is achieved and how individual segments are given specific identities is crucial to an understanding of both normal and defective formation of bone, muscle and nervous system. Recently, molecules belonging to the Notch signaling pathway have been implicated in playing a major role during the segmentation of vertebrate mesoderm and its morphological consequence, the formation of somites. Interestingly, the mRNA levels of several components of this pathway oscillate with a periodicity equal to that of somite formation. The oscillations are themselves coordinated into a wavefront that progresses anteriorly through the unsegmented, pre-somitic mesoderm and culminates in a fixed pattern of expression concomitant with the formation of each finished somite. The molecular role of individual Notch signaling pathway components during vertebrate segmentation and the function of their unusual cyclic pattern of expression is presently unknown. This study proposes to use the embryologically and genetically tractable zebrafish to gain an understanding of the function of these gene oscillations in the segmentation process. Currently, the migratory trajectories and fate commitment of the cells that undergo oscillations in the pre-somitic mesoderm are not known and this fundamental information is vital to any proposal for oscillatory function. Additionally, the availability of the zebrafish mutant line fused somites, which makes no mesodermal segments, allows for the study of interactions of the mRNA oscillations with the processes that confer segment polarity and boundary formation. The experiments in this proposal will contribute to a better understanding of the function of mRNA oscillations with respect to cell movement, fate commitment, the formation of boundaries and the formation of segment polarity in the pre-somitic mesoderm of vertebrates. The proposed findings will allow the construction of a more accurate model of the segmentation process, and are applicable to the understanding of any human syndrome with a segmentation defect.

最近，Notch配体的基因突变JAGGED1和DELTA-LIKE3被证明是两种人类不良疾病的原因，Alagille综合征和脊柱脊柱脊髓疾病。 在缺口途径中发现基因的基因在形成成人身体的骨骼和肌肉的组织中表现出动态的，振荡的表达模式，从而提供了对这些疾病的理解的新观点。 在包括人类在内的许多生物体中，重申的片段的形成是一个共同的主题。 进一步了解如何实现分割以及如何给予特定的特定身份，这对于理解骨，肌肉和神经系统的正常形成和有缺陷的形成至关重要。 最近，属于Notch信号通路的分子与在脊椎动物中胚层分割及其形态学后果的分割中起着主要作用。有趣的是，该途径的几个组成部分的mRNA水平振荡，其周期性等于节点的形成。 振荡本身被协调成一个波前，该波前通过未分段的，前的中胚层前部进展，并以固定的表达方式与每个成品体形成的固定表达方式达到顶点。 目前尚不清楚脊椎动物分割过程中单个Notch信号通路成分的分子作用以及其异常循环模式的功能。这项研究建议在分割过程中使用胚胎学和遗传上可牵引的斑马鱼，以了解这些基因振荡的功能。 当前，在前中胚层中进行振荡的细胞的迁移轨迹和命运承诺尚不清楚，并且这种基本信息对于任何振荡功能的建议至关重要。 此外，斑马鱼突变线融合的节点的可用性（不产生中胚片段）允许研究mRNA振荡与赋予片段极性和边界形成的过程的相互作用。 该提案中的实验将有助于更好地理解mRNA振荡在细胞运动，命运承诺，边界的形成以及脊椎动物前中胚层中段极性的形成方面的功能。 提出的发现将允许建立更准确的分割过程模型，并适用于以分割缺陷对任何人类综合症的理解。