title: Regulation of amino acid transporters in pluripotent cell populations in the embryo and in culture; novel roles for sodium-coupled neutral amino acid transporters.
abstract: The developmental outcomes of preimplantation mammalian embryos are regulated directly by the surrounding microenvironment, and inappropriate concentrations of amino acids, or the loss of amino acid-sensing mechanisms, can be detrimental and impact further development. A specific role for l-proline in the differentiation of embryonic stem (ES) cells, a cell population derived from the blastocyst, has been shown in culture. l-proline acts as a signalling molecule, exerting its effects through cell uptake and subsequent metabolism. Uptake in ES cells occurs predominantly through the sodium-coupled neutral amino acid transporter 2, Slc38a2 (SNAT2). Dynamic expression of amino acid transporters has been shown in the early mammalian embryo, reflecting functional roles for amino acids in embryogenesis. The expression of SNAT2 and family member Slc38a1 (SNAT1) was determined in mouse embryos from the 2-cell stage through to the early post-implantation pre-gastrulation embryo. Key changes in expression were validated in cell culture models of development. Both transporters showed temporal dynamic expression patterns and changes in intracellular localisation as differentiation progressed. Changes in transporter expression likely reflect different amino acid requirements during development. Findings include the differential expression of SNAT1 in the inner and outer cells of the compacted morula and nuclear localisation of SNAT2 in the trophectoderm and placental lineages. Furthermore, SNAT2 expression was up-regulated in the epiblast prior to primitive ectoderm formation, an expression pattern consistent with a role for the transporter in later developmental decisions within the pluripotent lineage. We propose that the differential expression of SNAT2 in the epiblast provides evidence for an l-proline-mediated mechanism contributing to the regulation of embryonic development.
authors.affiliation: School of BioSciences, University of Melbourne, 3010, Victoria, Australia; Stem Cells Australia, The University of Melbourne, 3010, Victoria, Australia.
authors.forename: Boon Siang Nicholas
authors.initials: BSN
authors.lastname: Tan
authors.affiliation: The Menzies Institute of Medical Research, University of Tasmania, Hobart, Tasmania 7001, Australia.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Rathjen
authors.affiliation: School of BioSciences, University of Melbourne, 3010, Victoria, Australia; Stem Cells Australia, The University of Melbourne, 3010, Victoria, Australia.
authors.forename: Alexandra J
authors.initials: AJ
authors.lastname: Harvey
authors.affiliation: School of BioSciences, University of Melbourne, 3010, Victoria, Australia; Stem Cells Australia, The University of Melbourne, 3010, Victoria, Australia.
authors.forename: David K
authors.initials: DK
authors.lastname: Gardner
authors.affiliation: School of BioSciences, University of Melbourne, 3010, Victoria, Australia; Stem Cells Australia, The University of Melbourne, 3010, Victoria, Australia; School of Medicine, University of Tasmania, Hobart, Tasmania 7001, Australia. Electronic address: joy.rathjen@utas.edu.au.
authors.forename: Joy
authors.initials: J
authors.lastname: Rathjen
mesh_terms: D026924:Amino Acid Transport System A / Q000235:genetics*; D000818:Animals; D002454:Cell Differentiation / Q000235:genetics*; D004622:Embryo, Mammalian; D047108:Embryonic Development / Q000235:genetics*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D000066450:Mouse Embryonic Stem Cells; D039904:Pluripotent Stem Cells / Q000378:metabolism; D011392:Proline / Q000378:metabolism; D055153:Stem Cell Niche / Q000235:genetics
chemical_list: D026924:Amino Acid Transport System A; C432411:Slc38a1 protein, mouse; C498798:Slc38a2 protein, mouse; D011392:Proline
keywords: Amino acid transporters; Pluripotent stem cells; Preimplantation embryo; Solute carrier 38 family; Trophoblast