title: Posttranscriptional control of the stem cell and neurogenic programs by the nonsense-mediated RNA decay pathway.
abstract: The mechanisms dictating whether a cell proliferates or differentiates have undergone intense scrutiny, but they remain poorly understood. Here, we report that UPF1, a central component in the nonsense-mediated RNA decay (NMD) pathway, plays a key role in this decision by promoting the proliferative, undifferentiated cell state. UPF1 acts, in part, by destabilizing the NMD substrate encoding the TGF-β inhibitor SMAD7 and stimulating TGF-β signaling. UPF1 also promotes the decay of mRNAs encoding many other proteins that oppose the proliferative, undifferentiated cell state. Neural differentiation is triggered when NMD is downregulated by neurally expressed microRNAs (miRNAs). This UPF1-miRNA circuitry is highly conserved and harbors negative feedback loops that act as a molecular switch. Our results suggest that the NMD pathway collaborates with the TGF-β signaling pathway to lock in the stem-like state, a cellular state that is stably reversed when neural differentiation signals that induce NMD-repressive miRNAs are received.
authors: Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA.
authors: Chih H
authors: CH
authors: Lou
authors: Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA.
authors: Ada
authors: A
authors: Shao
authors: Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA.
authors: Eleen Y
authors: EY
authors: Shum
authors: Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA.
authors: Josh L
authors: JL
authors: Espinoza
authors: Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA.
authors: Lulu
authors: L
authors: Huang
authors: Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA.
authors: Rachid
authors: R
authors: Karam
authors: Department of Reproductive Medicine, School of Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA; Institute of Genomic Medicine, University of California, San Diego, La Jolla, CA 92093-0695, USA. Electronic address: mfwilkinson@ucsd.edu.
authors: Miles F
authors: MF
authors: Wilkinson
mesh_terms: D000818:Animals; D001483:Base Sequence; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D025461:Feedback, Physiological; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism; D008969:Molecular Sequence Data; D058953:Neural Stem Cells / Q000166:cytology / Q000378:metabolism*; D055495:Neurogenesis; D059365:Nonsense Mediated mRNA Decay; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism; D015534:Trans-Activators / Q000235:genetics / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014981:Xenopus
chemical_list: D035683:MicroRNAs; C484446:Rent1 protein, mouse; D051906:Smad7 Protein; C497807:Smad7 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta