title: UPF2, a nonsense-mediated mRNA decay factor, is required for prepubertal Sertoli cell development and male fertility by ensuring fidelity of the transcriptome.
abstract: Nonsense-mediated mRNA decay (NMD) represents a highly conserved RNA surveillance mechanism through which mRNA transcripts bearing premature termination codons (PTCs) are selectively degraded to maintain transcriptomic fidelity in the cell. Numerous in vitro studies have demonstrated the importance of the NMD pathway; however, evidence supporting its physiological necessity has only just started to emerge. Here, we report that ablation of Upf2, which encodes a core NMD factor, in murine embryonic Sertoli cells (SCs) leads to severe testicular atrophy and male sterility owing to rapid depletion of both SCs and germ cells during prepubertal testicular development. RNA-Seq and bioinformatic analyses revealed impaired transcriptomic homeostasis in SC-specific Upf2 knockout testes, characterized by an accumulation of PTC-containing transcripts and the transcriptome-wide dysregulation of genes encoding splicing factors and key proteins essential for SC fate control. Our data demonstrate an essential role of UPF2-mediated NMD in prepubertal SC development and male fertility.
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS575, Reno, NV 89557, USA JianqiangBao@gmail.com wyan@medicine.nevada.edu.
authors.forename: Jianqiang
authors.initials: J
authors.lastname: Bao
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS575, Reno, NV 89557, USA.
authors.forename: Chong
authors.initials: C
authors.lastname: Tang
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS575, Reno, NV 89557, USA.
authors.forename: Shuiqiao
authors.initials: S
authors.lastname: Yuan
authors.affiliation: The Finsen Laboratory, Rigshospitalet, Faculty of Health Sciences, University of Copenhagen, Jagtvej 124, Copenhagen, DK-2200, Denmark Biotech Research and Innovation Centre (BRIC), University of Copenhagen, Jagtvej 124, Copenhagen, DK-2200, Denmark Danish Stem Cell Centre (DanStem), Faculty of Health Sciences, University of Copenhagen, Ole Maaløes Vej 5, Copenhagen N DK2200, Denmark.
authors.forename: Bo T
authors.initials: BT
authors.lastname: Porse
authors.affiliation: Department of Physiology and Cell Biology, University of Nevada School of Medicine, 1664 North Virginia Street, MS575, Reno, NV 89557, USA JianqiangBao@gmail.com wyan@medicine.nevada.edu.
authors.forename: Wei
authors.initials: W
authors.lastname: Yan
mesh_terms: D000818:Animals; D001483:Base Sequence; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D019295:Computational Biology; D003433:Crosses, Genetic; D005298:Fertility / Q000187:drug effects / Q000502:physiology*; D055786:Gene Knockout Techniques; D008297:Male; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D059365:Nonsense Mediated mRNA Decay / Q000502:physiology*; D016601:RNA-Binding Proteins; D060888:Real-Time Polymerase Chain Reaction; D017423:Sequence Analysis, RNA; D012708:Sertoli Cells / Q000166:cytology* / Q000378:metabolism; D013737:Testis / Q000254:growth & development / Q000378:metabolism; D059467:Transcriptome / Q000502:physiology*
chemical_list: D002352:Carrier Proteins; D016601:RNA-Binding Proteins; C529977:Upf2 protein, mouse
keywords: 3′UTR shortening; Alternative splicing; Gonocyte; Mouse; Nonsense-mediated mRNA decay; Premature termination codon; RNA-Seq; Sertoli cell; Spermatogenesis; Sterility; Testis