The KAP1 chromatin regulator and Paupar long non-coding RNA control subventricular zone neural stem cell maintenance and neurogenesis
Neural stem cells (NSCs) in the subventricular zone (SVZ) produce functional neurons throughout life and are an accessible and robust system to understand neurodevelopmental mechanisms. Elucidating the properties of NSCs will also provide insights for their use in the treatment of neurodevelopmental disorders and brain injuries. However, the epigenetic mechanisms that maintain NSCs and control neurogenesis remain unclear. We previously showed that Paupar, a CNS-expressed long non-coding RNA (lncRNA), controls neuroblastoma cell growth by binding and modulating the activity of the KAP1 transcription co-factor. We interrogated the last stages of olfactory bulb (OB) neurogenesis and showed that depletion of these two molecules in vivo reduced the number of newborn neurons and delayed their morphological differentiation. Here we investigated upstream functions of these two epigenetic regulators in SVZ NSCs self-renewal and neurogenesis. We combined studies using inducible knockout and in vivo knockdown electroporation, with molecular analysis. Our results demonstrate that KAP1 and Paupar are broadly expressed in the normal postnatal/adult SVZ neurogenic lineage, that they physically interact in SVZ cells and regulate NSC behaviour in the SVZ. KAP1 directly maintains the neural stem cell pool and regulates the expression of genes involved in the cell cycle. Paupar, in turn maintains stem cell quiescence by restricting lineage progression from stem cells to transit amplifying progenitors (TAPs). These results suggest important roles for a KAP1-Paupar containing chromatin regulatory complex in the control of SVZ NSC and SVZ-OB neurogenesis. Overall design: RNA-sequencing of KAP1 loss-of-function in neural stem cells generated from the SVZ and controls