Role of Ectodermal Signals in Facial Prominence Outgrowth and Development

外胚层信号在面部突出生长和发育中的作用

基本信息

批准号：
8281348
负责人：
TREVOR J WILLIAMS
金额：
$ 33.64万
依托单位：
UNIVERSITY OF COLORADO DENVER
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：
2009-07-01 至 2014-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8281348
关键词：
Address Affect Alleles Animal Model Automobile Driving Biological Models Biomedical Engineering Birds Calcium ion Cells Child Cleaved cell Clinic Congenital Abnormality Coupled Data Defect Development Developmental Process Diagnosis Ectoderm Embryo Embryonic Development Erinaceidae Event Evolution Face Family Fibroblast Growth Factor Frontonasal Prominence Future Gene Dosage Gene Expression Genetic Genetic Recombination Goals Growth Head Human Human Genetics Hyperplasia Individual Infant Knowledge Lead Mediating Medicine Mesenchyme Modeling Molecular Genetics Morphogenesis Morphology Mus Neural Crest Cell Neural tube Parents Pathway interactions Pattern Pattern Formation Pharmacologic Substance Phase Phenotype Population Prevention Process Quality of life Reagent Regulation Regulator Genes Research Role SHH gene Shapes Signal Pathway Signal Transduction Signal Transduction Pathway Signaling Molecule Skeleton Structure Surface Ectoderm Technology Testing Time Tissues Transgenes Undifferentiated Up-Regulation cell motility craniofacial dosage gain of function genetic analysis hedgehog signal transduction human SMO protein in utero insight knockout gene loss of function malformation mouse Cre recombinase mutant oral tissue orofacial precursor cell prevent protein function recombinase reconstruction skeletal smoothened signaling pathway

项目摘要

About 75% of birth defects involve the head, face, and oral tissues. Although orofacial clefts and other craniofacial malformations have clear environmental and genetic causes, insufficient information exists concerning the mechanisms of craniofacial development to enable the majority of these defects to be detected or prevented pre-natally. Our goal is to develop animal models of craniofacial malformations that will lead to mechanistic insight into the diagnosis and treatment of related human birth defects. The evolution and formation of the craniofacial skeleton relies on a specialized population of cells, the neural crest, arising at the margins of the neural tube during embryogenesis. While these cells contain significant intrinsic patterning information, they also rely on signals supplied by the surface ectoderm of the facial prominences to fulfill their growth and patterning potential. A number of studies, largely initiated using avian model systems, have demonstrated that several signal transduction pathways operating between the ectoderm and mesenchyme are critical for morphogenesis of the face. Indeed, manipulation of signaling cascades initiated by secreted factors belonging to the Fgf, Hedgehog (Hh), Wnt, and BMP families can alter the size and shape of the chick face. These studies have been much more challenging in the mouse due to its in utero development. Moreover, mouse gene knockouts affecting critical components of these signal transduction pathways die early in embryogenesis. Therefore, to study the function of these signaling events in later developmental processes - such as facial morphogenesis - it has been necessary to employ conditional gene knockout technology. A number of Cre recombinase transgenes can target gene expression in the developing facial ectoderm, but most are limited by the extent and/or timing of their expression. Recently, we generated a new Cre recombinase transgene, Crect, which circumvents many of these problems. Crect can mediate recombination in the entire embryonic ectoderm prior to E9.5 and is highly specific for this tissue layer and its derivatives. Preliminary data obtained using conditional alleles of Fgf8, Ctnnb1 (¿-catenin), and Shh with Crect have shown the importance of the expression of these signaling molecules in the ectoderm for facial patterning. These studies have also revealed extensive cross-talk between these pathways in shaping the face. Thus, the goal of this application is to determine how these proteins function individually and as a network in the ectoderm to regulate craniofacial formation. In Aim I we will use Crect to investigate the role of Wnt/¿-catenin signaling in the ectoderm for development of the face. In Aim II we will perform a similar analysis on the Hh pathway. In Aim III we will test the interplay of these two pathways with Fgf8. The results of these analyses will reveal how these signaling pathways interact to control mouse craniofacial morphogenesis and will provide significant insight into the regulation of facial growth and patterning pertinent to the study of human birth defects and facial reconstruction.

大约75％的先天缺陷涉及头部，面部和口腔组织。颅面畸形具有明显的环境和遗传原因，存在不足的信息关于大多数这些DESECT的颅面发育机制。或以前的预防。我们的目标是开发颅类动物对相关人类出生缺陷的诊断和信任的机械洞察力。颅面骨骼的进化和形成依赖于专门的细胞种群神经rest，在胚胎发生过程中在神经管的边缘出现。重要的固有图案信息，它们也在由由面部突出物以实现其增长和图案潜力。鸟类模型系统已经证明了您之间的严重性传导途径外胚层和间质对面部的形态发生是批判性的。由属于FGF，刺猬（HH）和Bmilies的分泌因素发起的级联反应可能会改变小鸡面的大小和形状在鼠标中更具挑战性此外，子宫开发。转导途径在胚胎发生早期死亡。在以后的发展过程中 - 例如面部形态发生 - 使用有条件的基因敲除技术。在发展中的事务中，但大多数受其表达的程度和/或时间的限制。最近，我们产生了一种新的Cre Cre Cre Rebimbinase转基因，即Crect，该转基因绕过许多问题。在E9.5之前，菌株可以介导整个胚胎外胚层的重组，并且非常具体组织层及其衍生物。 SHH带有截然的SHH表明了excoderm的expsessese信号分子的重要性对于面部图案，这些研究也嘲笑这些途径因此，塑造面部。 ASA网络在AIM中定期的颅面形成。 Wnt/¿的角色 - 在Ectoderm中为AIM的发育中的蛋白宁。在AIM III中的HH途径分析分析的信号通路如何相互作用以控制小鼠颅面形态发生，并将为面部生长的调节和与 Stuman的先天缺陷和面部重建。