PNKP is required for maintaining the integrity of progenitor cell populations in adult mice.

DNA repair proteins are critical to the maintenance of genomic integrity. Specific types of genotoxic factors, including reactive oxygen species generated during normal cellular metabolism or as a result of exposure to exogenous oxidative agents, frequently leads to "ragged" single-strand DNA breaks. The latter exhibits abnormal free DNA ends containing either a 5'-hydroxyl or 3'-phosphate requiring correction by the dual function enzyme, polynucleotide kinase phosphatase (PNKP), before DNA polymerase and ligation reactions can occur to seal the break. Pnkp gene deletion during early murine development leads to lethality; in contrast, the role of PNKP in adult mice is unknown. To investigate the latter, we used an inducible conditional mutagenesis approach to cause global disruption of the Pnkp gene in adult mice. This resulted in a premature aging-like phenotype, characterized by impaired growth of hair follicles, seminiferous tubules, and neural progenitor cell populations. These results point to an important role for PNKP in maintaining the normal growth and survival of these murine progenitor populations.

A tale of two cousins: Ependymal cells, quiescent neural stem cells and potential mechanisms driving their functional divergence.

Recent work has suggested that stem cells exhibit far greater heterogeneity than initially thought. Indeed, their dynamic nature and shared traits with surrounding niche cells have made prospective identification of adult neural stem cells (NSCs) challenging. Refined fate mapping strategies and single-cell omics techniques have begun to clarify functionally distinct states within the adult NSC pool, the molecular signatures that govern these states, and the functional contributions/interactions with neighboring cells within the subventricular niche. Ependymal cells are the epithelial cells which line the ventricular system and reside in the same niche as NSCs. Our own work has revealed that, despite sharing similar embryonic origins with NSCs and close geographic proximity, ependymal cells are transcriptionally distinct and fail to exhibit stem cell function in vivo, even following injury. Intriguingly, comparison of ependymal cells with qNSCs revealed transcriptional signatures that are largely overlapping, suggesting that post-transcriptional regulation might underlie their divergent phenotypes. Additional analysis of ependymal versus qNSC gene regulatory network activation supports this notion. This Viewpoint summarizes the historical confusion regarding the identity of NSCs within the lateral ventricle niche and describes recent work that provides greater appreciation for the diverse functional states within the NSC niche.