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Bowen, Margot Elizabeth

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Bowen

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Margot Elizabeth

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Bowen, Margot Elizabeth
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    Applying Next Generation Sequencing to Skeletal Development and Disease
    (2014-02-25) Bowen, Margot Elizabeth; Warman, Matthew L.; Kronenberg, Henry; Olsen, Bjorn; Pacifici, Maurizio
    Next Generation Sequencing (NGS) technologies have dramatically increased the throughput and lowered the cost of DNA sequencing. In this thesis, I apply these technologies to unresolved questions in skeletal development and disease. Firstly, I use targeted re-sequencing of genomic DNA to identify the genetic cause of the cartilage tumor syndrome, metachondromatosis (MC). I show that the majority of MC patients carry heterozygous loss-of-function mutations in the PTPN11 gene, which encodes a phosphatase, SHP2, involved in many signaling pathways. Furthermore, I show that cartilage lesions in MC patients likely arise following somatic second-hit mutations in PTPN11. Secondly, I use RNA-seq to identify gene expression changes that occur following genetic inactivation of Ptpn11 in mouse chondrocyte cultures. I show that chondrocytes lacking Ptpn11 fail to properly undergo terminal differentiation and instead continue to express genes associated with earlier stages of chondrocyte maturation. I validate these findings in vivo by examining markers of specific chondrocyte maturation stages in the vertebral growth plates of mice following postnatal mosaic inactivation of Ptpn11. Together, my results provide insight into the molecular mechanisms underlying the initiation and growth of cartilage tumors. In the third component of my thesis, I develop a method to map and clone zebrafish mutations by performing whole genome sequencing on pooled DNA. I apply this method to zebrafish mutants identified in a mutagenesis screen for adult phenotypes, including skeletal phenotypes, and determine that a nonsense mutation in bmp1a underlies the craniofacial phenotype in the wdd mutant. In summary, I show that NGS technologies can be successfully utilized to firstly identify the genetic cause of a human skeletal disorder, secondly investigate the molecular mechanisms regulating the maturation of skeletal cells, and thirdly expedite the process of mapping and cloning zebrafish mutants with skeletal phenotypes. Altogether, my research provides insight into the pathways and processes regulating skeletal development and disease.
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    Presphenoidal synchondrosis fusion in DBA/2J mice
    (Springer-Verlag, 2012) Adams, Allysa Claire; McBratney-Owen, Brandeis; Newby, Brittany; Bowen, Margot Elizabeth; Olsen, Bjorn; Warman, Matthew
    Cranial base growth plates are important centers of longitudinal growth in the skull and are responsible for the proper anterior placement of the face and the stimulation of normal cranial vault development. We report that the presphenoidal synchondrosis (PSS), a midline growth plate of the cranial base, closes in the DBA/2J mouse strain but not in other common inbred strains. We investigated the genetics of PSS closure in DBA/2J mice by evaluating F1, F1 backcross, and/or F1 intercross offspring from matings with C57BL/6J and DBA/1J mice, whose PSS remain open. We observed that PSS closure is genetically determined, but not inherited as a simple Mendelian trait. Employing a genome-wide SNP array, we identified a region on chromosome 11 in the C57BL/6J strain that affected the frequency of PSS closure in F1 backcross and F1 intercross offspring. The equivalent region in the DBA/1J strain did not affect PSS closure in F1 intercross offspring. We conclude that PSS closure in the DBA/2J strain is complex and modified by different loci when outcrossed with C57BL/6J and DBA/1J mice. Electronic supplementary material The online version of this article (doi:10.1007/s00335-012-9437-8) contains supplementary material, which is available to authorized users.