Abstract
The neural fate commitment of pluripotent stem cells requires the repression of extrinsic inhibitory signals and the activation of intrinsic positive transcription factors. However, how these two events are integrated to ensure appropriate neural conversion remains unclear. In this study, we showed that Pou3f1 is essential for the neural differentiation of mouse embryonic stem cells (ESCs), specifically during the transition from epiblast stem cells (EpiSCs) to neural progenitor cells (NPCs). Chimeric analysis showed that Pou3f1 knockdown leads to a markedly decreased incorporation of ESCs in the neuroectoderm. By contrast, Pou3f1-overexpressing ESC derivatives preferentially contribute to the neuroectoderm. Genome-wide ChIP-seq and RNA-seq analyses indicated that Pou3f1 is an upstream activator of neural lineage genes, and also is a repressor of BMP and Wnt signaling. Our results established that Pou3f1 promotes the neural fate commitment of pluripotent stem cells through a dual role, activating internal neural induction programs and antagonizing extrinsic neural inhibitory signals.
Highlights
Vertebrate development is the process by which unrestricted pluripotent stem cells progressively make lineage fate choices
Our in vitro and in vivo data indicate that Pou3f1 is crucial for embryonic stem cells (ESCs) neural fate commitment and promotes the transition from epiblast stem cells (EpiSCs) to neural progenitor cells
The Pou3f1 gene expression profiles in mouse embryos in vivo (Figure 3; Zwart et al, 1996) and of ESC differentiation in vitro (Figure 1, Figure 1—figure supplement 1) imply that Pou3f1 may participate in early neural development
Summary
Vertebrate development is the process by which unrestricted pluripotent stem cells progressively make lineage fate choices. Gastrulation initiates at embryonic day (E) 6.5. A portion of the anterior ectoderm is specified to adopt the neural fate and subsequently, develops into the neuroectoderm, forming a plate-shaped structure called the neural plate at approximately E7.5 (Tam and Zhou, 1996). Previous studies have indicated that neural fate specification from embryonic ectoderm occurs autonomously in the absence of inhibitory signals such as bone morphogenetic proteins (BMPs) and Wnts (Munoz-Sanjuan and Brivanlou, 2002; Stern, 2005b). In early Xenopus, chick, and mouse embryos, BMP and Wnt signals prevent neural conversion and contribute to non-neural fates such as
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