Psi controls neural stem cell fate in the developing Drosophila brain

Abstract

Oligodendroglioma (ODG) is a diffuse adult glioma molecularly defined by the IDH1/2 mutation and 1p/19q codeletion. Although slow growing, ODG recurs and remains incurable. Genetically, FUBP1 ranks in the top 23% of predicted ODG driver mutations with predicted loss-of-function, suggesting anti-proliferative functions in the brain. Counterintuitively, given the predicted tumour suppressor function in the brain, FUBP1, was initially discovered as a transcriptional activator of the MYC oncogene. Consistent with conserved pro-proliferative functions, the Drosophila FUBP1 ortholog (Psi) interacts with the transcriptional Mediator complex, to integrate developmental signals, and drive a network of genes (including Myc) to promote proliferative growth in the wing epithelium. This observation does not, however, provide a rationale for FUBP1's tumour suppressor function in the brain.

Here we demonstrate Psi functions as a tumour suppressor in the Drosophila brain; Psi knockdown (KD) drives NSC lineage expansion, characterised by accumulation of specific progenitor populations. Psi's direct binding targets in the NSC lineage, identified using Targeted DamID (TaDa), were intersected with genes differentially expressed in Psi KD NSCs to reveal Psi directly regulates expression of factors governing NSC renewal and differentiation. Of note, the transcriptional regulator implicated in stem cell fate control, HmgZ (HMG) and Sox21a (SoxB) are normally repressed by Psi in the NSC lineage. HmgZ co-KD partially suppressed the progenitor expansion phenotype associated with Psi KD, whereas Sox21a co-KD did not significantly suppress this phenotype. Future studies investigating potential roles for the HmgZ orthologue(s) in FUBP1-mutant oligodendroglioma will be of much interest. Show more