title: The mevalonate pathway regulates primitive streak formation via protein farnesylation.
abstract: The primitive streak in peri-implantation embryos forms the mesoderm and endoderm and controls cell differentiation. The metabolic cues regulating primitive streak formation remain largely unknown. Here we utilised a mouse embryonic stem (ES) cell differentiation system and a library of well-characterised drugs to identify these metabolic factors. We found that statins, which inhibit the mevalonate metabolic pathway, suppressed primitive streak formation in vitro and in vivo. Using metabolomics and pharmacologic approaches we identified the downstream signalling pathway of mevalonate and revealed that primitive streak formation requires protein farnesylation but not cholesterol synthesis. A tagging-via-substrate approach revealed that nuclear lamin B1 and small G proteins were farnesylated in embryoid bodies and important for primitive streak gene expression. In conclusion, protein farnesylation driven by the mevalonate pathway is a metabolic cue essential for primitive streak formation.
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.|Division of Medicinal Safety Science, National Institute of Health Sciences, 1-18-1 Kamiyoga, Setagaya-ku, Tokyo, Japan.
authors.forename: Yoshimi
authors.initials: Y
authors.lastname: Okamoto-Uchida
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: Ruoxing
authors.initials: R
authors.lastname: Yu
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: Norio
authors.initials: N
authors.lastname: Miyamura
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: Norie
authors.initials: N
authors.lastname: Arima
authors.affiliation: Chemical Biology Screening Center, Institute of Biomaterials and Bioengineering, TMDU, Tokyo, Japan.
authors.forename: Mari
authors.initials: M
authors.lastname: Ishigami-Yuasa
authors.affiliation: Chemical Biology Screening Center, Institute of Biomaterials and Bioengineering, TMDU, Tokyo, Japan.|Department of Organic and Medicinal Chemistry, Institute of Biomaterials and Bioengineering, TMDU, Tokyo, Japan.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Kagechika
authors.affiliation: Department of Chemical Bioscience, Institute of Biomaterials and Bioengineering, TMDU, Tokyo, Japan.
authors.forename: Suguru
authors.initials: S
authors.lastname: Yoshida
authors.affiliation: Department of Chemical Bioscience, Institute of Biomaterials and Bioengineering, TMDU, Tokyo, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Hosoya
authors.affiliation: Laboratory of Cytometry and Proteome Research, TMDU, Tokyo, Japan.
authors.forename: Makiko
authors.initials: M
authors.lastname: Nawa
authors.affiliation: Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, TMDU, Tokyo, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Kasama
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Asaoka
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Reiner Wimmer
authors.initials: RW
authors.lastname: Alois
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Elling
authors.affiliation: IMBA, Institute of Molecular Biotechnology of the Austrian Academy of Sciences, Vienna, Austria.
authors.forename: Josef M
authors.initials: JM
authors.lastname: Penninger
authors.affiliation: Department of Ophthalmology and Laboratory for Visual Science, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Sachiko
authors.initials: S
authors.lastname: Nishina
authors.affiliation: Department of Ophthalmology and Laboratory for Visual Science, National Center for Child Health and Development, Tokyo, Japan.
authors.forename: Noriyuki
authors.initials: N
authors.lastname: Azuma
authors.affiliation: Department of Developmental and Regenerative Biology, Medical Research Institute, Tokyo Medical and Dental University (TMDU), 1-5-45 Yushima, Bunkyo-ku, Tokyo, Japan.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Nishina
mesh_terms: D000818:Animals; D002454:Cell Differentiation; D015536:Down-Regulation / Q000235:genetics; D058732:Embryoid Bodies; D018507:Gene Expression Regulation, Developmental; D053858:Metabolic Networks and Pathways; D055442:Metabolome; D055432:Metabolomics; D008798:Mevalonic Acid / Q000378:metabolism*; D008813:Mice, Inbred ICR; D032383:Myocytes, Cardiac / Q000166:cytology / Q000378:metabolism; D055495:Neurogenesis; D020411:Oligonucleotide Array Sequence Analysis; D038081:Organogenesis; D054240:Primitive Streak / Q000196:embryology* / Q000378:metabolism*; D017368:Protein Prenylation; D015027:Zebrafish
chemical_list: D008798:Mevalonic Acid