title: A mesodermal factor, T, specifies mouse germ cell fate by directly activating germline determinants.
abstract: Germ cells ensure reproduction and heredity. In mice, primordial germ cells (PGCs), the precursors for spermatozoa and oocytes, are induced in pluripotent epiblast by BMP4 and WNT3, yet the underlying mechanism remains unclear. Here, using an in vitro PGC specification system, we show that WNT3 induces many transcription factors associated with mesoderm in epiblast-like cells through β-CATENIN. Among these, T (BRACHYURY), a classical and conserved mesodermal factor, was essential for robust activation of Blimp1 and Prdm14, two of the germline determinants. T, but not SMAD1 or TCF1, binds distinct regulatory elements of both Blimp1 and Prdm14 and directly upregulates these genes, delineating the downstream PGC program. Without BMP4, a program induced by WNT3 prevents T from activating Blimp1 and Prdm14, demonstrating a permissive role of BMP4 in PGC specification. These findings establish the key signaling mechanism for, and a fundamental role of a mesodermal factor in, mammalian PGC specification.
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Shinya
authors: S
authors: Aramaki
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Precursory Research for Embryonic Science and Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan.
authors: Katsuhiko
authors: K
authors: Hayashi
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Kazuki
authors: K
authors: Kurimoto
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Hiroshi
authors: H
authors: Ohta
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan.
authors: Yukihiro
authors: Y
authors: Yabuta
authors: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.
authors: Hiroko
authors: H
authors: Iwanari
authors: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.
authors: Yasuhiro
authors: Y
authors: Mochizuki
authors: Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Komaba 4-6-1, Meguro-ku, Tokyo 153-8904, Japan.
authors: Takao
authors: T
authors: Hamakubo
authors: Laboratory of Genome Structure and Function, Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
authors: Yuki
authors: Y
authors: Kato
authors: Laboratory of Genome Structure and Function, Center for Epigenetic Disease, Institute of Molecular and Cellular Biosciences, The University of Tokyo, Yayoi 1-1-1, Bunkyo-ku, Tokyo 113-0032, Japan.
authors: Katsuhiko
authors: K
authors: Shirahige
authors: Department of Anatomy and Cell Biology, Graduate School of Medicine, Kyoto University, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Exploratory Research for Advanced Technology, Japan Science and Technology Agency, Yoshida-Konoe-cho, Sakyo-ku, Kyoto 606-8501, Japan; Center for iPS Cell Research and Application, Kyoto University, 53 Kawahara-cho, Shogoin Yoshida, Sakyo-ku, Kyoto 606-8507, Japan; Institute for Integrated Cell-Material Sciences, Kyoto University, Yoshida-Ushinomiya-cho, Sakyo-ku, Kyoto 606-8501, Japan. Electronic address: saitou@anat2.med.kyoto-u.ac.jp.
authors: Mitinori
authors: M
authors: Saitou
mesh_terms: D000818:Animals; D001755:Blastocyst / Q000166:cytology; D055415:Bone Morphogenetic Protein 4 / Q000378:metabolism; D004268:DNA-Binding Proteins; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000378:metabolism*; D044127:Epigenesis, Genetic / Q000502:physiology; D005260:Female; D005326:Fetal Proteins / Q000235:genetics / Q000378:metabolism*; D018507:Gene Expression Regulation, Developmental; D005854:Germ Cells / Q000166:cytology* / Q000378:metabolism*; D008297:Male; D008648:Mesoderm / Q000166:cytology / Q000378:metabolism; D008817:Mice, Mutant Strains; D000074462:Positive Regulatory Domain I-Binding Factor 1; D011247:Pregnancy; D016601:RNA-Binding Proteins; D015398:Signal Transduction / Q000502:physiology; D020825:T-Box Domain Proteins / Q000235:genetics / Q000378:metabolism*; D014157:Transcription Factors / Q000378:metabolism; D060508:Wnt3 Protein / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000098908:Brachyury Protein
chemical_list: D055415:Bone Morphogenetic Protein 4; D004268:DNA-Binding Proteins; D005326:Fetal Proteins; D000074462:Positive Regulatory Domain I-Binding Factor 1; D016601:RNA-Binding Proteins; D020825:T-Box Domain Proteins; D014157:Transcription Factors; D060508:Wnt3 Protein; D051176:beta Catenin; D000098908:Brachyury Protein; C525810:Bmp4 protein, mouse; C495267:CTNNB1 protein, mouse; C513258:Prdm1 protein, mouse; C531066:Prdm14 protein, mouse; C555508:Wnt3 protein, mouse