Exome capture sequencing of low-grade oligodendrogliomas identified loss-of-function mutations in the single stranded nucleic acid binding protein FUBP1. Although GWAS analysis predicts these are oligodendroglioma drivers, functional studies are essential to determine mechanisms for FUBP1-driven glioma. As oligodendroglioma is a heterogeneous tumour driven by glioma stem cells in the brain neural microenvironment, mechanistic studies must take stem cell-niche interactions into account. Thus, we have developed Drosophila brain models to delineate neural stem cell-niche interactions in vivo. Our exciting preliminary data revealed knockdown of the FUBP1 ortholog Psi specifically in the neural stem cell (NSC) niche, comprised of cortex glia, drives NSC overproliferation. Thus, FUBP1/Psi is required in the niche to promote differentiation of NSCs, consistent with predicted tumour suppressor functions in glioma.
Lineage-specific genome-wide binding and expression studies to determine the transcriptional targets of FUBP1/Psi in the glial niche mediating the cell-non-autonomous stem cell expansion, identified the critical determinant of neighbouring cell fate, Notch. As a direct target of Psi repression in the glial niche, we predicted Notch mediates the non-autonomous NSC expansion. Surprising, however, Notch knockdown in the niche did not suppress the FUBP1/Psi-dependent NSC expansion phenotype. Moreover, niche-specific depletion of Notch was not only sufficient to non-autonomously drive neural stem and progenitor cell expansion, but actually enhanced the NSC overproliferation phenotype driven by niche-specific Psi depletion. Thus, NSC expansion driven by the FUBP1/Psi-depleted niche is unlikely dependent on Notch de-repression. We are currently testing the hypothesis that Notch depletion in the glial niche increases availability, and signalling, of Notch ligands (Delta and Serrate) in neighbouring NSCs. This project provides insight into the complexities of NSC-niche interactions, even in a simple genetic model, and highlights the importance of understanding the molecular basis of FUBP1 function in normal development to appreciate the mechanisms of FUBP1-driven glioma.