Establishing Left-Right Asymmetry in Vertebrates

建立脊椎动物的左右不对称性

• 批准号: 8606224
• 负责人: Cammon ARRINGTON
• 金额: $ 13.72万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-01 至 2015-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8606224
• 关键词: Binding; Biological Models; Cardiac; Cardiovascular system; Cells; Child; Cilia; Complex; Congenital Heart Defects; Defect; Detection; Development; Extracellular Fluid; Gastrula; Gene Expression; Genes; Genetic; Handedness; Heart; Heparan Sulfate Proteoglycan; Human; Lateral; Lead; Left; Mesoderm; Modeling; Molecular; Molecular Genetics; Morbidity - disease rate; Morphogenesis; Mus; Nodal; Organ; Organogenesis; Pathway interactions; Pattern; Play; Positioning Attribute; Process; Role; Side; Structure; System; Testing; Tube; Vertebrates; Vesicle; Zebrafish; base; cilium biogenesis; congenital heart disorder; epithelial to mesenchymal transition; fibroglycan; fluid flow; improved; malformation; mortality; precursor cell; public health relevance

DESCRIPTION (Provided by Applicant): Strong conservation of heart formation along the left-right (LR) axis among vertebrates suggests that common developmental mechanisms and genetic pathways exist for left-right development. However, despite abundant evidence supporting a role for nodal monocilia in the establishment of LR asymmetry, little is known about formation of the late gastrula node. In zebrafish, the node equivalent is Kupffer's vesicle (KV). KV contains monocilia, generates asymmetric fluid flow, and is necessary for left-sided expression of downstream laterality genes. Because KV is easily visualized and experimentally manipulated in zebrafish, the candidate will use this model system to better understand KV formation and its role in LR development. From preliminary studies, he has discovered that syndecan-2, a single-pass transmembrane heparan sulfate proteoglycan, is required for normal LR development and plays a cell-autonomous role in KV formation. Morpholino knockdown of syndecan-2 causes reversal of heart and gut looping and leads to misshapen KV with fewer and shorter cilia. Based on these observations, the candidate proposes to further define the role of syndecan-2 in KV and cilia formation/function and explore the necessary molecular interactions of syndecan-2 during the process of KV development. Through this study, genetic and molecular mechanisms that regulate cardiac LR development will be discovered and one day used to improve detection and treatment of congenital heart disease in children. PUBLIC HEALTH RELEVANCE: Abnormalities in left-right development often lead to complex congenital heart defects with significant associated morbidity and mortality, but little is known about the molecular anomalies that cause these defects. Understanding the mechanisms that regulate left-right development in model vertebrate systems will advance our ability to understand, detect, and treat human cardiovascular malformations.

描述(申请人提供)：脊椎动物心脏形成沿左-右(LR)轴的强烈保守性表明，左右发育存在共同的发育机制和遗传途径。然而，尽管大量的证据支持结节单纤毛在LR不对称性的建立中的作用，但对晚期原肠胚结节的形成知之甚少。在斑马鱼中，相当于节点的是库普弗氏囊泡(KV)。KV含有单纤毛，产生不对称的流体流动，是下游偏侧基因左侧表达所必需的。由于KV很容易在斑马鱼身上可视化和实验操作，候选人将使用这个模型系统来更好地了解KV的形成及其在LR发育中的作用。从初步研究中，他发现Syndecan-2，一种单次通过的跨膜硫酸乙酰肝素蛋白多糖，是正常LR发育所必需的，并在KV的形成中发挥细胞自主作用。Syndecan-2的吗啡敲除会导致心脏和肠循环的逆转，并导致纤毛较少和较短的畸形KV。基于这些观察，候选人建议进一步确定Syndecan-2在KV和纤毛形成/功能中的作用，并探讨Syndecan-2在KV发育过程中必要的分子相互作用。通过这项研究，将发现调节心脏LR发育的遗传和分子机制，并有一天将用于改善儿童先天性心脏病的检测和治疗。 公共卫生相关性：左向右发育异常经常导致复杂的先天性心脏缺陷，并与显著相关的发病率和死亡率，但对导致这些缺陷的分子异常知之甚少。了解在模型脊椎动物系统中调节左右发育的机制将提高我们理解、检测和治疗人类心血管畸形的能力。

项目成果

Rer1p maintains ciliary length and signaling by regulating γ-secretase activity and Foxj1a levels.

• DOI: 10.1083/jcb.201208175
• 发表时间: 2013-03-18
• 期刊: The Journal of cell biology
• 作者: Jurisch-Yaksi N;Rose AJ;Lu H;Raemaekers T;Munck S;Baatsen P;Baert V;Vermeire W;Scales SJ;Verleyen D;Vandepoel R;Tylzanowski P;Yaksi E;de Ravel T;Yost HJ;Froyen G;Arrington CB;Annaert W
• 通讯作者: Annaert W