Brain tumors arise when brain cells fail to mature properly or fail to remain into their respective cell types and lose their identities. Oligodendroglioma is a type of brain cancer where the CIC gene, which codes for the capicua (CIC) protein, is often found to be mutated. Additionally, previous studies report that a loss of CIC in certain brain regions results in an increased number of immature brain cells. Guided by these findings, the authors hypothesize that CIC plays a key role in the development and maturation of brain cells.

The researchers first established that CIC is essential for brain development when they observed impaired growth and decreased brain volume in mice where CIC was deleted from precursor brain cells. They also found that CIC is mainly involved in the regulation of neurons, not other types of supporting cells in the brain, as most of the genes affected due to CIC deletion were related to the development of neurons. Furthermore, the authors measured CIC levels in adult brain regions where the generation of new neurons takes place and found a progressive increase in CIC levels, with lower amounts of CIC in immature precursor brain cells, and higher expression in the mature neurons. The authors also discovered that if CIC is deleted from precursor cells, normal cell growth occurs, however none of the cells mature. Together these results emphasize the role of CIC in the maturation of neurons.

CIC is a protein that regulates the abundance of other proteins, therefore the researchers looked at these proteins to determine their role in the maturation of neurons. Deletion of CIC causes an increase in a growth factor named VGF (another protein which is known to be involved in the maturation of neurons). Increase in the amount of VGF impairs the ability of progenitor cells to specialize into neurons, which is also seen with the deletion of CIC. Consequently, a decrease in VGF is able to partially restore abnormal neuronal maturation due to the loss of CIC. This reveals that the role of CIC in brain cell maturation is mediated through VGF.

The authors also investigated proteins that interact with CIC and found that CIC mediates its functions through a number of protein interactions to regulate the packaging of genetic materials, which in turn affects maturation of brain cells. In conclusion, this research reveals the role of CIC in the maturation of neurons. These findings further emphasize that CIC is necessary for normal brain development. Finally, VGF as a mediator of CIC function presents as a potential therapeutic target in brain cancers associated with immature brain cells.

Reference:

Hwang I. et al. CIC is a critical regulator of neuronal differentiation. JCI Insight. 5(9), 2020. Link to the full text article.