Dbx2, an aging-related homeobox gene, inhibits the proliferation of adult neural progenitors

Abstract

The subventricular zone (SVZ) of the adult mouse brain contains quiescent neural stem cells, which can be activated (aNSCs) to generate transit amplifying progenitors (TAPs), neuroblasts (NBs) and newborn neurons. Neurogenesis declines during aging, as the aged SVZ niche causes transcriptomic changes that promote NSC quiescence and decrease proliferating neural/stem progenitor cells (NSPCs). The transcription factors mediating these changes, however, remain unclear. We previously found that the homeobox gene Dbx2 is upregulated in aged SVZ NSPCs and inhibits NSPC culture growth. Here, we report that Dbx2 is repressed by Epidermal Growth Factor Receptor signaling, which promotes NSPC proliferation and decreases in the aged SVZ. We show that Dbx2 inhibits NSPC proliferation by hindering the G2/M transition and elucidate the transcriptomic networks modulated by Dbx2, highlighting its role in the downregulation of the cell cycle molecular pathways. Accordingly, Dbx2 function is negatively correlated with the transcriptional signatures of proliferative NSPCs (aNSCs, TAPs and early NBs). These results point to Dbx2 as a molecular node relaying the anti-neurogenic input of the aged niche to the NSPC transcriptome.