UCSF

Neural stem cells in the brain give rise to both neurons and glia cells during embryonic development and help maintain tissue homeostasis in adulthood. Although transcription factors and intracellular signaling pathways that modulate NSC function in embryonic and adult brain have been heavily studied, in vivo functions of long noncoding RNAs (lncRNAs) and chromatin regulators in NSCs are still poorly understood. Pnky is a nuclear-enriched lncRNA that is transcribed divergently from the neighboring proneural transcription factor Pou3f2. In the embryonic cortex, I found that Pnky deletion increases neuronal differentiation and depletes NSCs prematurely, resulting in defects in cortical laminar structure in postnatal mice. Pnky expression from a bacterial artificial chromosome (BAC) transgene rescues the in vivo phenotypes of Pnky-deleted brains, supporting the idea that Pnky acts in trans as a key regulator of NSC function and neurogenesis in the embryonic cortex. Chromatin regulator JMJD3 is a histone demethylase implicated in development and disease of multiple organs. My studies show that Jmjd3-deletion in the hippocampus results in depletion of adult NSCs. During development, Jmjd3-deleted dentate gyrus precursors precociously differentiate into neurons, resulting in failed establishment of the hippocampal NSC niche. Single cell RNA-sequencing reveals a broad disruption of genes involved in maintaining stem cell function in Jmjd3-deleted NSCs. In the adult brain, loss of Jmjd3 similarly leads to precocious neuronal differentiation, reflecting the loss of gene expression signatures related to stem cell maintenance. These data indicate both lncRNA-Pnky and JMJD3 may control the rate of neurogenesis, acting like a cell-intrinsic clock for NSCs.