<i>Klf5</i> regulates the transition from apical radial glia to intermediate progenitor cells in the developing mammalian brain

Krüppel-like factors (Klfs) are DNA-binding transcriptional factors that regulate multiple physiological features, including the cell cycle, cell differentiation, and tissue organization. Among them, Klf2, Klf4, and Klf5 are crucial for the induction and maintenance of pluripotent stem cells. However, the roles of these factors in maintaining neural stem cells remain poorly understood. Here, we show that Klf5 plays a dominant role in maintaining neural precursor cell (NPC) populations by suppressing their differentiation and radial migration in developing mouse brains of either sex. Klf5 also regulates the proliferation of NPCs and promotes differentiation of Pax6⁺ apical radial glia in the ventricular zone to Eomes⁺ (Tbr2⁺) intermediate progenitor cells in the subventricular zone (SVZ) by upregulating <i>Hes1</i> and <i>Eomes</i> expression. Overexpression of <i>Klf5</i> in NPCs reduced the pool of quiescent neural stem cells (NSCs) in the postnatal brain, resulting in attenuated neurogenesis in the subependymal zone and the dentate gyrus of the hippocampus in the adult brain. <i>Klf5</i>-overexpressing male mice exhibited impaired memory formation and reduced preference for social novelty. Our findings suggest a mechanism by which NPCs expand the output of differentiating cells through intermediate progenitor populations.<b>Significance Statement</b> NPCs in the mammalian developing brain take one of two fates: a few NPCs elongate their cell cycle time and become quiescent NSCs, whereas the others differentiate into intermediate progenitor cells. However, the molecular mechanisms underlying this fate choice remain largely unknown. Intermediate progenitor cells proliferate to provide appropriate numbers of neurons and glia. The number of divisions of intermediate progenitor cells is much larger in primates than in rodents, providing a cellular basis for the expansion of the outer SVZ and for the massive production of neurons and glia in the primate brain, leading to gyrification of the primate cortex. In this study, we investigated the role of <i>Klf5</i> in the generation and proliferation of intermediate progenitor cells.