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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

基本信息

批准号：
10213691
负责人：
Thomas F Schilling
金额：
$ 48.58万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-04-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10213691
关键词：
Address African Animals Biological Assay Birds Bone Morphogenetic Proteins Cartilage Cartilage injury Cell Polarity 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 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 osteoprogenitor cell planar cell polarity response skeletal skeletal disorder skeletal disorder therapy skeletal dysplasia skeletogenesis smoothened signaling pathway stem cell therapy stem cells

项目摘要

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.

项目总结

项目成果

期刊论文数量（50）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Small-scale marker-based screening for mutations in zebrafish development.

基于标记的小规模斑马鱼发育突变筛查。

DOI：
10.1007/978-1-60327-483-8_34
发表时间：
2008
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
0
作者：
Currie,PeterD;Schilling,ThomasF;Ingham,PhilipW
通讯作者：
Ingham,PhilipW

A show of Hands: Novel and conserved expression patterns of teleost hand paralogs during craniofacial, heart, fin, peripheral nervous system and gut development.

DOI：
10.1002/dvdy.380
发表时间：
2021-12
期刊：
Developmental dynamics : an official publication of the American Association of Anatomists
影响因子：
0
作者：
Reynolds S;Pierce C;Powell B;Kite A;Hall-Ruiz N;Schilling T;Le Pabic P
通讯作者：
Le Pabic P

Wnt signaling interacts with bmp and edn1 to regulate dorsal-ventral patterning and growth of the craniofacial skeleton.