Grant: Project Grant

Oligodendrocytes are cells in the brain that make myelin to help nerve cells send signals to each another. Oligodendrogliomas are malignant brain tumours composed of cells resembling early immature oligodendrocytes. Recently, the gene CIC has been found to be mutated in most oligodendrogliomas, and this change is suspected to be important in how oligodendrogliomas arise and how they behave. But what CIC does, and why oligodendrogliomas may arise when this gene is altered remain unknown. Recently, using a mouse model in which we genetically deleted CIC, we showed that CIC loss increases the proliferation of the very earliest and most primitive of cells in the brain, the neural stem cells. Loss of CIC also biases the stem cells to start to become early oligodendrocytes. Interestingly, however, these increased early oligodendrocytes appear to be trapped in a proliferative immature state and do not progress to form non-dividing myelin-generating cells. These as-yet-undescribed functions for CIC are important to understand, as cancer is not only a problem of overproduction of stem-like cells but also a problem of their survival and failed maturation. We hypothesize that CIC functions as a key tumour suppressor in oligodendrogliomas through its regulation of neural stem cell and oligodendrocyte precursor proliferation, and its requirement for progression to mature oligodendrocytes - thus leading to an excess of cells that form a tumour when CIC is lost. Our project aims to: 1) Gain a comprehensive view of OPC differentiation and population dynamics regulated by CIC 2) Determine the contribution of CIC-ETV5 to cell cycle control in OPCs and ODG 3) Identify molecular mechanisms by which the CIC-ETV5 axis maintains malignancy in ODG Our work will shed light on the biology of a poorly understood brain tumour, has the potential to reveal new functions of for this recently identified gene, and may point to new therapeutic strategies for brain tumours.