UCSF

While it is now appreciated that certain long noncoding RNAs (lncRNAs) have important functions in cell biology, relatively few have been shown to regulate development in vivo, particularly with genetic strategies that establish cis versus trans mechanisms. We have identified Pinky (Pnky) as a lncRNA that regulates neurogenesis in the embryonic and postnatal mouse brain. Pnky is a nuclear-enriched lncRNA that is divergent to the neighboring proneural transcription factor Pou3f2. In postnatal neural stem cells (NSCs) from the ventricular-subventricular zone (V-SVZ), Pnky knockdown promotes neuronal lineage commitment and expands the transit amplifying cell population, increasing neuron production several-fold. In the embryonic cortex, Pnky knockdown increases neuronal differentiation and depletes the NSC population prematurely. Furthermore, genetic deletion of Pnky results in the aberrant production of neuronal masses along the postnatal V-SVZ. In the developing cortex, Pnky regulates the production of projection neurons from NSCs in a cell-autonomous manner, and loss of Pnky alters postnatal cortical lamination. Surprisingly, Pou3f2 expression is not disrupted by deletion of the entire Pnky gene. Moreover, expression of Pnky from a bacterial artificial chromosome (BAC) transgene rescues the differential gene expression and increased neurogenesis of Pnky-knockout NSCs, as well as the developmental phenotypes of Pnky-deletion in vivo. Thus, despite being transcribed divergently from a key developmental transcription factor, the lncRNA Pnky regulates neural development in trans.