Glioblastoma (GBM) is the most aggressive form of glioma, the most common primary brain cancer in adults. GBM is highly resistant to standard radiotherapy and chemotherapy treatments and thus represents a leading cause of cancer-related death worldwide. Although many genetic alterations have been identified for GBM, its histogenesis is still poorly understood. The relative contribution of each genetic alteration and their downstream effects, as well as the sequence of molecular and cellular events required for tumor formation, are not well known. My group is interested in understanding the cellular and molecular mechanisms that underlie the formation of high-grade gliomas such as GBM. My previous work has identified the transcriptional regulator Id4 as a factor that inhibits tumor growth and antagonizes the tumorigenic effects of Olig2, a key regulator of GBM development. However, Id4 has also been shown to drive tumorigenesis. In my first objective (Aim 1), I propose to clarify the role of Id4 in gliomagenesis. Using genetically defined mouse models of glioma and primary GBM cultures, I will test whether Id4 function varies depending on the cellular and molecular context of the cell of origin. In my second objective (Aim 2), I propose to characterize the successive stages leading from the transformation of cells of origin to tumor development, and the individual and combined contributions of defined genetic alterations. I will use a mouse glioma model in which one can label, in a time- and cell type-specific manner, neural cells in which defined genetic alterations are introduced. The proposed project will better define how the genetic and cellular contexts can influence the function of a transcriptional regulator, such as Id4, in gliomagenesis. In addition, the project will give further insights into the molecular and cellular mechanisms that underlie the formation of GBM, which will lead to the identification of new therapeutic targets.