Role and Regulation of Cellular Polarity in Craniofacial Skeletogenesis

细胞极性在颅面骨骼发生中的作用和调节

• 批准号: 9982927
• 负责人: Thomas F Schilling
• 金额: $ 52.81万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-01 至 2022-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982927
• 关键词: Address; African; Animals; Biological Assay; Birds; Bone Morphogenetic Proteins; Cartilage; Cartilage injury; Cell Polarity; Cell Therapy; Cell Transplantation; Cell physiology; Cells; Chondrocytes; Cichlids; Clinical; Comparative Study; Complement; Congenital Abnormality; Defect; Development; Diagnosis; Disease; Distal; Dorsal; Embryo; Embryonic Development; Epiphysial cartilage; Epithelial; Epithelium; Erinaceidae; Event; FAT3 gene; Fatty acid glycerol esters; Funding; Future; Genes; Genetic; Genetic study; Growth; Heterotopic Ossification; Human; Hypertrophy; Laboratories; Larva; Link; Location; Mandible; Maps; Mesenchymal; Mesenchymal Stem Cells; Methods; Modeling; Molecular; Morphogenesis; Morphology; Mosaicism; Mus; Mutation; Orbital separation excessive; Pathway interactions; Pattern; Pharmacology; Phenotype; Physical condensation; Physiologic Ossification; Process; Quantitative Trait Loci; Robinow syndrome; Role; Shapes; Signal Pathway; Signal Transduction; Site; Skeletal Development; Skeletal system; Skeleton; Testing; Time; Transgenic Organisms; Van Maldergem syndrome; WNT Signaling Pathway; WNT5A gene; Work; Zebrafish; bone; cartilage cell; cartilage development; cell growth regulation; cell type; craniofacial; craniofacial bone; craniofacial development; cranium; gain of function; genetic manipulation; imaging genetics; improved; insight; intercalation; joint formation; joint injury; long bone; malformation; mutant; novel; planar cell polarity; progenitor; response; skeletal; skeletal disorder; skeletal disorder therapy; skeletal dysplasia; skeletogenesis; smoothened signaling pathway; stem cells

Project Summary A functional skeletal system depends on the coordinated development of cartilages and bones during embryogenesis. However, little is known about the cellular and molecular mechanisms that control the polarized growth of cartilages, which determine endochondral bone size and shape. Unraveling the signals that direct mesenchymal cells to condense and align into pre-chondrogenic stacks is key to understanding early events that shape the organization and growth of the skeleton. Elucidating these processes will allow better diagnosis and treatments for skeletal malformations and birth defects. Moreover, molecules that control cartilage morphogenesis and differentiation may be of considerable clinical importance both for improvements in diagnosing and treating congenital birth defects as well as developing mesenchymal stem cell based therapies for skeletal disorders. Our recent finding that planar cell polarity pathways are essential for cartilage cells to stack properly, suggests a previously unappreciated mechanism for patterning cartilage growth plates of long bones as well as growth zones in bones of the skull. Dramatic results from our laboratory now demonstrate that Hedgehog signaling, well known for its critical roles in long bone growth plates, also regulates cartilage polarity in zebrafish. Embryos deficient in Hedgehog signaling show defects in cartilage stacking. Moreover, comparisons of cartilage growth zones in African cichlid fishes that have evolved dramatically different craniofacial bone shapes, reveal that growth zone size differences during larval development correlate with these species-specific shapes. Aim 1 will build upon our previously funded work to address the hypothesis that Hedgehog signaling regulates growth zone patterning via planar cell polarity. Cartilage phenotypes will be evaluated in embryos and larvae in which Hedgehog signaling has been manipulated pharmacologically or genetically. We will identify the polarity pathways regulated by Hedgehog as well as the signaling and responding cells. Aim 2 will address the functions of polarity in growth zones, including modes of propagation, responsiveness to Hedgehog, and roles in the perichondrium. For this we have new transgenics with which we can track polarity, and methods for targeting perichondrial cells. Finally, Aim 3 will focus on a new “evo-devo” project in the lab, discovering new genes involved in cartilage polarity and growth zones using quantitative trait locus mapping in cichlids. Together, these studies will lead to mechanistic insights into the relatively unexplored functions of cellular polarity in endochondral bones of the vertebrate skeleton. This work will lead to insights into the causes of human skeletal disorders of Hedgehog signaling, such as brachydactyly, as well as polarity disorders such as Robinow and Van Maldergem syndromes.

项目摘要 一个有功能的骨骼系统取决于在发育过程中软骨和骨骼的协调发育。 胚胎发生然而，关于控制这些细胞的细胞和分子机制知之甚少。 软骨的极化生长，决定了软骨内骨的大小和形状。Unraveling the 引导间充质细胞凝聚并排列成软骨形成前的细胞堆的信号是 了解塑造骨骼组织和生长的早期事件。阐明这些 这一进程将有助于更好地诊断和治疗骨骼畸形和出生缺陷。 此外，控制软骨形态发生和分化的分子可能是相当重要的。 临床重要性，无论是在诊断和治疗先天性出生缺陷的改善，以及 开发用于骨骼疾病的基于间充质干细胞的疗法。我们最近发现， 平面细胞极性通路对于软骨细胞正确堆叠是必不可少的， 用于形成长骨的软骨生长板以及生长区的未被认识的机制 在头骨中。我们实验室的戏剧性结果现在表明，刺猬信号， 以其在长骨生长板中的关键作用而闻名，也调节斑马鱼的软骨极性。 缺乏Hedgehog信号的胚胎显示软骨堆积的缺陷。此外，比较 软骨生长区在非洲慈鲷鱼已经演变出显着不同的颅面 骨骼形状，揭示了幼虫发育过程中生长区大小的差异与这些 物种特有的形状。目标1将以我们之前资助的工作为基础来解决这一假设 Hedgehog信号通过平面细胞极性调节生长区模式。卡氏表型 将在操纵Hedgehog信号的胚胎和幼虫中进行评估 或者基因上。我们也将确定Hedgehog调控的极性通路 作为信号和响应细胞。目标2将讨论极性在生长区中的作用， 包括传播模式、对Hedgehog的反应以及在软骨膜中的作用。为此 我们有了新的转基因药物，可以追踪极性， 细胞最后，Aim 3将专注于实验室中的一个新的“evo-devo”项目，发现参与基因组的新基因。 软骨极性和生长区的数量性状基因定位在慈鲷。所有这些 研究将导致对细胞极性相对未探索的功能的机械见解， 脊椎动物骨骼的软骨内骨。这项工作将有助于深入了解人类疾病的原因。 Hedgehog信号传导的骨骼疾病，例如短指（趾）畸形，以及极性疾病，例如 Robinow和货车Maldergem综合征。