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Elucidating the role of Wnt/PCP signaling in craniofacial cartilage development

阐明 Wnt/PCP 信号在颅面软骨发育中的作用

基本信息

批准号：
7897608
负责人：
Rodney Michael Dale
金额：
$ 5.3万
依托单位：
LURIE CHILDREN'S HOSPITAL OF CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
2009
资助国家：
美国
起止时间：
2009-09-01 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7897608
关键词：
Address Animal Model Behavior Behavior Control Breathing Cartilage Cell Polarity Cells Cephalic Child Childhood Chondrocytes Cilia Cleaved cell Cleft Lip Cleft Palate Clinic Confocal Microscopy Congenital Abnormality Cytoskeleton Defect Deglutition Development Diagnosis Disease Elements Embryo Fishes Foundations Future Genes Genetic Genetic screening method Glypican Goals Growth Head Human Immunohistochemistry In Vitro Infant Knowledge Laboratories Lead Life Link Live Birth Methods Modeling Molecular Morphogenesis Movement Neural Crest Operative Surgical Procedures Outcome Pathway interactions Play Positioning Attribute Prevention Process Qualifying Respiratory Tract Infections Role Saints Shapes Signal Pathway Signal Transduction Signaling Molecule Skeleton Stem cells Structure Techniques Testing Tissues Transgenic Organisms United States Vertebrates Work Zebrafish base cartilage development cilium biogenesis craniofacial cranium experience gastrulation improved in vivo innovation intercalation interest malformation member migration mutant new therapeutic target novel marker public health relevance receptor repaired research study retinal rods teleost

项目摘要

DESCRIPTION (provided by applicant): Our laboratory is interested in the role that Wnt/PCP signaling plays in the morphogenetic processes that are required for cartilage formation. We utilize the powerful and innovative combination of genetic, embryological, and molecular methods uniquely available for the teleost, Danio rerio, zebrafish to address this question. Two genes involved in the Wnt/PCP pathway that are of interest to us wnt 5b and glypican 4 (gpc4). Wnt5b is one of the key activators of the PCP pathway, while gpc4 is likely a Wnt co-receptor. Zebrafish mutant for wnt 5b and gpc4 have be identified and are observed with shorter body axis, attributed to wnt 5b and gpc4 requirement for proper convergance and extension movement during gastrulation, and craniofacial skeleton malformation. We find zebrafish mutant in either of these genes have craniofacial chondrocytes that are unable to intercalate properly and therefore do not form organized rod-like cartilage structures. The goal of our future experiments is to elucidate the developmental step(s) in which wnt 5b and glypican 4 are necessary for proper cartilage morphogenesis. We are also interested in recent work suggesting an interplay between Wnt/PCP signaling and primary cilia. Intriguingly, many of the characterized human ciliopathies have some form of cranial defect. A secondary goal of our work will be to determine if there is an interaction between primary cilia and Wnt/PCP signaling in cartilage formation. We will use our wnt 5b and glypican 4 mutant zebrafish to test for genetic interactions. Public Health Relevance: Approximately 1 in every 1000 live births in the United States present with some form of craniofacial defect, including cleft lip and cleft palate. Infants with cleft disorders are more susceptible to respiratory infections and suffer from difficulties in breathing, swallowing, and speaking, which require the child to have multiple corrective surgeries to be able to live a normal life. Many of the congenital craniofacial defects seen in the clinic are caused by the abnormal morphogenesis and migration of the progenitor cells that will form the cranial skeleton. By studying the conserved mechanisms that form the craniofacial skeleton in vertebrate animal models we will be able to improve the diagnosis, treatment and prevention of these common occurring pediatric malformations.

描述（由申请人提供）：我们的实验室对 Wnt/PCP 信号在软骨形成所需的形态发生过程中发挥的作用感兴趣。我们利用针对硬骨鱼、斑马鱼和斑马鱼独有的遗传、胚胎学和分子方法的强大且创新的组合来解决这个问题。我们感兴趣的两个参与 Wnt/PCP 途径的基因是 wnt 5b 和磷脂酰肌醇蛋白聚糖 4 (gpc4)。 Wnt5b 是 PCP 途径的关键激活剂之一，而 gpc4 可能是 Wnt 共受体。已鉴定出 WNT 5b 和 gpc4 的斑马鱼突变体，并观察到其体轴较短，这归因于 Wnt 5b 和 gpc4 在原肠胚形成期间需要适当的会聚和伸展运动，以及颅面骨骼畸形。我们发现这些基因中任一基因的斑马鱼突变体具有无法正确插入的颅面软骨细胞，因此不能形成有组织的杆状软骨结构。我们未来实验的目标是阐明 wnt 5b 和磷脂酰肌醇蛋白聚糖 4 对于适当的软骨形态发生所必需的发育步骤。我们还对最近提出 Wnt/PCP 信号传导与初级纤毛之间相互作用的研究感兴趣。有趣的是，许多具有特征的人类纤毛病都具有某种形式的颅骨缺陷。我们工作的第二个目标是确定初级纤毛和软骨形成中 Wnt/PCP 信号之间是否存在相互作用。我们将使用 wnt 5b 和磷脂酰肌醇蛋白聚糖 4 突变斑马鱼来测试遗传相互作用。公共卫生相关性：在美国，大约每 1000 名活产婴儿中就有 1 人患有某种形式的颅面缺陷，包括唇裂和腭裂。患有唇腭裂疾病的婴儿更容易受到呼吸道感染，并出现呼吸、吞咽和说话困难，这需要孩子进行多次矫正手术才能过上正常的生活。临床上看到的许多先天性颅面缺陷是由形成颅骨的祖细胞的异常形态发生和迁移引起的。通过研究脊椎动物模型中形成颅面骨骼的保守机制，我们将能够改善这些常见儿科畸形的诊断、治疗和预防。