The role of the piRNA pathway in mouse neocorticogenesis

PIWI-interacting RNAs (piRNAs) and their associated PIWI proteins play an important role in repressing transposable elements in animal germlines. However, there have been conflicting reports about piRNA expression and function in the soma, particularly in the brain. Here we investigated the role of piRNAs and an important PIWI family member, Piwi-like protein 1 (Piwil1; also known as Miwi in mouse) in the developing mouse neocortex. Using a Piwil1 knock-out mouse strain, we found that Piwil1 is essential for neocorticogenesis, including neocortical cell cycle, migration and dendritogenesis. Piwil1 deletion resulted in increased cell cycle re-entry at embryonic day 17 (E17) when predominantly intracortically projecting neurons are being produced. Prenatal Piwil1 deletion increased the number of Pax6+ radial glia at postnatal day 0 (P0) and disrupted migration of Satb2+ neurons within deep layers at E17, P0 and P7. Satb2+ neurons showed increased co-localization with Bcl11b, marker of subcortically projecting neurons. In addition, Piwil1 knock-outs have disrupted neocortical circuitry represented by thinning of the corpus callosum and altered dendritogenesis. These results are consistent with the rodent phenotypes reported by a recent study that mainly used RNAi knockdown experiments. We identified a disrupted set of genes associated with cell cycle, cell adhesion, transcription and migration in developing neocortices. We further investigated the potential role of piRNAs by sequencing piRNAs in developing neocortices in the wildtype and Piwil1 knock-out strain. Unexpectedly, we did not find a strong signal of absolute piRNA abundance or differential expression in the knock-out, suggesting that Piwil1 may act independently of piRNAs in mouse neocorticogenesis. Our results may help clarify some outstanding questions in the piRNA field about the role of the piRNA pathway in the brain.