Conditional Inactivation of Pen-2 in the Developing Neocortex Leads to Rapid Switch of Apical Progenitors to Basal Progenitors

The transition of apical progenitors (APs) to basal progenitors (BPs) is an important neurogenic process during cortical expansion. Presenilin enhancer 2 (Pen-2, also named as Psenen) is a key subunit of γ-secretase and has been implicated in neurodevelopmental disease. However, it remains unknown how Pen-2 may regulate the maintenance of APs. To address this question, we generated a conditional KO (cKO) mouse in which Pen-2 is specifically inactivated in neural progenitor cells in the telencephalon. Both male and female embryos were used. We show thatPen-2cKO cortices display remarkable depletion of Aps, but transient increase on BPs, compared with controls. We demonstrate that the proliferation rate of APs or BPs is not changed, but the switch of APs to BPs is dramatically accelerated inPen-2cKO cortices. Molecular analyses reveal decreased levels of Hes1 and Hes5 but increased levels of Ngn2 and NeuroD1 inPen-2KO cells. We report that expression of Notch1 intracellular domain inPen-2cKO cortices restores the population of APs and BPs. In summary, these findings highlight a central role of the Notch signaling in Pen-2-dependent maintenance of neural stem cells in the developing neocortex. SIGNIFICANCE STATEMENTPresenilin enhancer 2 (Pen-2) has been implicated in neurodevelopmental disease. However, mechanisms by which Pen-2 regulates cortical development are not understood. In this study, we generated neural progenitor cell-specificPen-2conditional KO mice. We observe depletion of apical progenitors and transiently increased the number of basal progenitors in the developing neocortex of Pen-2 mutant mice. Mechanistic analyses reveal decreased levels of Hes1 and Hes5, but increased levels of neurogenic transcription factors in Pen-2 mutant cortices, compared with controls. We demonstrate that reintroduction of Notch intracellular domain into mutant mice restores the population of apical progenitors to basal progenitors. The above findings strongly suggest that the Pen-2-Notch pathway plays an essential role in the maintenance of neural stem cells during cortical development.