The role of Twisted Gastrulation in Mouse Development

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DESCRIPTION (provided by applicant): Dr. Petryk is a pediatric endocrinologist at the University of Minnesota. The candidate's long-term goal is to pursue an academic career devoted primarily to basic research. As a pediatric resident and an endocrinology fellow, Dr. Petryk was involved in the care of a significant number of patients with congenital malformations and growth disorders. Her interest in the molecular basis of these health problems led her to pursue research training in developmental biology in order to gain understanding of their pathogenesis as a basis for possible therapeutic interventions in the future. Dr. Petryk has generated twisted gastrulation (tsg) deficient mice that will serve as a model to study molecular and cellular mechanisms of skeletal and neural tube development. This work will be carried out under the mentorship of Dr. Michael O'Connor. Dr. Petryk has also established key collaborations that will be instrumental in her career development plan. Tsg has recently been recognized as a new bone morphogenetic protein (BMP) antagonist that is required for normal embryonic development of invertebrate and lower vertebrate species. Tsg is thought to act synergistically with another extracellular protein Chordin (Chd) to inhibit BMP2 and BMP4 signaling by preventing their binding to the receptors. The role of Tsg in mammalian development is currently unknown. Preliminary phenotypic analysis indicates that Tsg-deficient mice have reduced growth and skeletal defects similar to those that occur in spina bifida. Chd-deficient mice also have skeletal defects and abnormal neural tube patterning. The comparison of the phenotypes of mice deficient in Chd versus those deficient in Tsg, and generation of Tsg;Chd double mutants, will offer new insight into the molecular mechanisms of congenital malformations. The candidate will pursue the following specific aims: 1) Characterize the mechanisms underlying the skeletal defects and growth deficiency in Tsg-deficient mice; 2) Understand the interactions between Tsg and Chd in mouse embryonic development by generating and characterizing Tsg;Chd double mutants.