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

Cheng, SS; Liu, TT; Hu, YM; Xia, YQ; Hou, JX; Huang, CL; Zou, XC; Liang, J; Shi, YS; Zheng, YL; Lu, J; Chen, GQ

Chen, GQ (reprint author), Nanjing Univ, Model Anim Res Ctr, MOE Key Lab Model Anim Dis Study, State Key Lab Pharmaceut Biotechnol,Inst Brain Sc, Nanjing 210061, Jiangsu, Peoples R China.; Lu, J (reprint author), Jiangsu Normal Univ, Sch Life Sci, Key Lab

JOURNAL OF NEUROSCIENCE, 2019; 39 (12): 2195

Abstract

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 gamma-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 that Pen-2 cKO 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 in Pen-2 cKO cortices. Molecular analyses reveal decreased levels of Hes1 and Hes5 but increased levels of Ngn2 and NeuroD1 in Pen-2 KO cells. We report that expression of Notch1 intracellular domain in Pen-2 cKO 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.

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