The Function And Mechanism Of Mst1 And Mst2 In Mouse Embryo And Treg Development

Mst1 and Mst2 (Mst1/2) genes encode two highly conserved serine/therine kinases in mammals. Previous studies in low model organisms and cells have demonstrated that Mst1/2 were involved in many signal pathways to regulated cell proliferation and apoptosis. The Investigation of Mst1/2 deficient mice revealed redundant functions of Mst1/2 in tumorigenesis, while study of Mstl deficient mice demonstrated critical roles of Mstl in T cell migration and homing. However, whether Mst1/2 also have other important physiological functions are not clear. In this thesis, we investigate the function of Mstl and Mst2 in mouse embryo development, immune tolerance maintenance and the development of regulatory T cells.Congenital birth defects are big threats for human health and quality of the population. Studies on embryonic development will help us to understand the molecular mechanisms underlying the birth defects. We found that Mst1/2 DKO mice died between E9.5-E10.5 with defects of neural tube closure and cardiovascular development. These results indicated that Mst1/2 might play important roles in development of embryonic tissues including neural tube and cardiovascular. However, Mst1/2 neural-specific deficient mice can survive to adult with normal development of neural tube. In addition, the cardiovascular development of E10.5 Mst1/2 endothelial-specific deficient mice is also normal. Our further analysis revealed the placenta trophoblast giant cells in Mst1/2 DKO mice were severely increased while the spongiotrophobalst were dramatically reduced. The labyrithine development of Mst1/2 DKO embryos were severe retarded. We also observed expression of Mash2, which is critical for placenta development, was significantly reduced in Mst1/2 DKO placenta. Therefore, we conclude that the severe developmental defects of placenta are the major reasons leading to embryonic lethality of Mst1/2 DKO embryos. These studies not only broadened our knowledge of control of embryo development, but also may provide new clues for the design of therapeutic strategy for placenta related diseases.Regulatory T cell is a kind of T cells, which has immune suppress function. It plays important role in the control of autoimmunity. But the molecular mechanisms underlying regulatory T cell development are not fully understood yet. We found that Mst1-/-mice were prone to develop autoimmune disease. Our mixed bone marrow transplantation experiments demonstrated loss of dominant immune tolerance could be the major reason leading to autoimmunity in Mst1-/-mouse. We also observed that the development and function of Treg cells were impaired in Mst1-/-mouse. Further mechanistic studies showed that Mstl could maintain the stability of Foxo1 and Foxo3a through directly phosphorylating them and indirectly antagonizing the phosphorylation of Akt. These results demonstrate that Mstl positively regulates Foxp3 expression, regulatory T cell development and maintain proper immune tolerance. Finally, we showed that Mst1 and Mst2 played partial redundant roles in Treg development and immune tolerance maintenance. Our studies revealed the novel function of Mstl and Mst2 in Treg development and immune tolerance. At the same time, our findings will shed light on the treatment of autoimmune disease.