title: AMD1 is essential for ESC self-renewal and is translationally down-regulated on differentiation to neural precursor cells.
abstract: The gene expression networks governing embryonic stem cell (ESC) pluripotency are complex and finely regulated during differentiation toward specific lineages. We describe a new role for Amd1 (adenosyl methionine decarboxylase), a key enzyme in the polyamine synthesis pathway, in regulating both ESC self-renewal and differentiation to the neural lineage. Amd1 is highly expressed in ESCs and is translationally down-regulated by the neural precursor cell (NPC)-enriched microRNA miR-762 during NPC differentiation. Overexpression of Amd1 or addition of the polyamine spermine blocks ESC-to-NPC conversion, suggesting Amd1 must be down-regulated to decrease the levels of inhibitory spermine during differentiation. In addition, we demonstrate that high levels of Amd1 are required for maintenance of the ESC state. We show that forced overexpression of Amd1 in ESCs results in maintenance of high Myc levels and a delay in differentiation on removal of LIF. We propose that Amd1 is a major regulator of ESC self-renewal and that its essential role lies in its regulation of Myc levels within the cell.
authors.affiliation: Institute of Medical Biology, Agency for Science, Technology, and Research, Immunos, Singapore.
authors.forename: Dawei
authors.initials: D
authors.lastname: Zhang
authors.forename: Tianyun
authors.initials: T
authors.lastname: Zhao
authors.forename: Haw Siang
authors.initials: HS
authors.lastname: Ang
authors.forename: Peini
authors.initials: P
authors.lastname: Chong
authors.forename: Ryotaro
authors.initials: R
authors.lastname: Saiki
authors.forename: Kazuei
authors.initials: K
authors.lastname: Igarashi
authors.forename: Henry
authors.initials: H
authors.lastname: Yang
authors.forename: Leah A
authors.initials: LA
authors.lastname: Vardy
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000235:genetics* / Q000378:metabolism*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D015536:Down-Regulation; D053595:Embryonic Stem Cells / Q000166:cytology* / Q000201:enzymology*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D035683:MicroRNAs / Q000378:metabolism; D009474:Neurons / Q000166:cytology / Q000201:enzymology; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism
chemical_list: D035683:MicroRNAs; D016271:Proto-Oncogene Proteins c-myc; D012437:Adenosylmethionine Decarboxylase