Regulation of cell signaling by Col11a1 during craniofacial development in the ze

DESCRIPTION (provided by applicant): The purpose of this study is to investigate the molecular and cellular mechanisms that regulate vertebrate development using a zebrafish model system. Collagen type XI plays an essential role in skeletal development, as demonstrated by Stickler syndrome and Marshall syndrome, which can be attributed to mutations in the COL11A1 gene. Changes in craniofacial development, vision, as well as hearing loss are hallmark features of Stickler and Marshall syndromes. Preliminary studies indicate that zebrafish, developing under conditions of reduced concentrations of Col11a1, may model certain aspects of Stickler and Marshall syndrome. Therefore, zebrafish studies will not only allow us to understand the role of Col11a1 in normal vertebrate development, but in addition, to understand the embryonic molecular and cellular events that lead to the symptoms of Stickler and Marshall syndromes, as well as other related congenital birth defects. In addition to the structural role that collagen type XI plays in the regulation of collagen fibrillogenesis, the investigator proposes a function in cellular differentiation. To delineate this proposed function, she will determine if Col11a1 affects the rate and extent of proliferation in pre-chondrocytic cells during craniofacial development. Additionally, she will determine if Col11a1 alters the rate of osteoblast maturation and mineralization. The process of chondrogenesis and osteogenesis are coordinately regulated during skeletal development in all vertebrates, by common signaling pathways, including those mediated by bone morphogenetic proteins. The results of the proposed studies are likely to provide a more thorough understanding of the role of Col11a1 in BMP-induced osteogenesis and chondrogenesis during craniofacial development in the zebrafish. The identification of new molecular targets for improved diagnosis and early intervention provides the potential to ameliorate the consequences of birth defects. PUBLIC HEALTH REELEVANCE: The impact of extracellular matrix-related congenital diseases of the skeleton in general, total hundreds of millions of dollars per year. The significance of extracellular matrix and collagen is illustrated by some of the most debilitating congenital diseases such as osteogenesis imperfecta, Ehlers Danlos syndrome, Stickler syndrome, Marshall syndrome, and many of the chondrodysplasias. In spite of the importance during development, relatively little is known about how the extracellular matrix functions during skeletal development. By using recent discoveries and new technologies, the investigator hopes to increase the understanding of the normal process of healthy development, so that in the event that the process of skeletal development goes awry, problems can be detected early and treated so as to avoid or treat birth defects and the associated health risks that are often present throughout life.