Adolescent idiopathic scoliosis (AIS) is the most common pediatric spinal deformity, which affects 2-3% of school age children and often necessitates medical intervention such as bracing or surgery. Despite a significant burden to children, parents and health care systems;the etiology of AIS is poorly understood. In part, this is due to a lack of genetically tractable animal models of scoliosis. For this reason, I will investigate cellular and molecular mechanisms of the formation and progression of axial curvatures in a novel dominant insertional zebrafish mutant, druk. Interestingly, druk displays possible corollaries to human AIS such as progressive curvature of the axial column without malformation of vertebrae beginning at larval stages. I have determined that two genes, mon1a and mstr1rb, immediately flanking the druk insertion exhibit transcriptional upregulation in druk mutant fish. I hypothesize that druk produces a molecular gain-of-function of one or both flanking genes. I will directly test if overexpression of these genes is sufficient to generate axil curvatures in larval fish. Multiple mechanisms have been proposed for AIS including loss of myotendenous connections along the axial column as well as generalized loss of bone mineral density (BMD). X-ray microtomography (?-CT) analysis of adult druk fish showed a significant decrease in BMD of the axial column. I hypothesize that abnormal bone metabolism may precede the progression of druk induced axial curvature. To test this, I will ask if the activity o osteoclasts, osteoblasts or the abnormal development of myotendinous junctions along the axial column contributes to the druk mutant phenotype. This proposal aims to define the cellular and molecular mechanisms of the origin and progression of genetically tractable axial column curvatures in a larval zebrafish, akin to characteristics of AIS in humans. These results may provide genetic evidence of a scoliosis locus that will assist early detection in humans. Finally, the druk mutant will enhance our understanding of the etiology of scoliosis and possibly serve as a model for the development of novel pharmacological therapies to combat AIS in humans.
Adolescent idiopathic scoliosis (AIS) is characterized by the appearance of mild to severe curvature of the axial spinal column without malformations of individual vertebrae. I will characterize a novel dominant zebrafish mutant as a model of AIS, by defining the genetic, cellular and tissue level mechanisms of scoliosis progression. These experiments will provide fundamental insights into the molecular, cellular and tissue level defects leading to the progression of scoliosis in a highly tractable genetic model organism and, ultimately, also serve as a model for better understanding of scoliosis progression in humans.
|Karner, Courtney M; Long, Fanxin; Solnica-Krezel, Lilianna et al. (2015) Gpr126/Adgrg6 deletion in cartilage models idiopathic scoliosis and pectus excavatum in mice. Hum Mol Genet 24:4365-73|
|Gray, Ryan S; Wilm, Thomas P; Smith, Jeff et al. (2014) Loss of col8a1a function during zebrafish embryogenesis results in congenital vertebral malformations. Dev Biol 386:72-85|