Grant: Operating Grant

Oligodendroglioma is a malignant brain cancer, and it is thought to arise from immature cells in the brain called oligodendrocyte progenitor cells. These cells, which are normally present during the formation and growth of the brain, are under the complex control of specialized signals from growth factors. Too little growth factor signaling can lead to underdevelopment of the brain whereas too much growth factor signaling can lead to the development of cancer. Recently, my colleagues and I have identified a gene called Capicua (CIC) that is mutated in almost all oligodendrogliomas and that is likely to play a role in the initiation or progression of the oligodendroglioma by regulating how cells behave in the presence or absence of growth factors and in the presence of changes in other genes. The goal of this project is to understand what CIC does normally in the brain, and what happens when CIC is lost or mutated. My hypothesis is that CIC controls the decisions that normal stem cells make - decisions that include whether to proliferate or not, and whether they should become one type of brain cell or another. Thus, loss or mutation of CIC could result in deregrulated growth that results in oligodendroglioma. My lab has generated a new mutant mouse strain in which we can disrupt CIC in the cells of our choice. We will use this mouse to ablate CIC in various cells I the developing and mature brain, and ask whether CIC controls proliferation or cell fate specification. We will also use this mouse and introduce other mutations to determine if we can make a robust and genetically relevant mouse model of oligodendroglioma. Finally, we will search for the molecular mechanisms by which CIC can regulate oligodendrocyte progenitor growth. Our studies may point to new targets for therapy of oligodendroglioma and may result in a much-needed animal model of oligodendroglioma that can be used for preclinical testing.