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      Bovine blastocyst development depends on threonine catabolism

      Najafzadeh, V.; Henderson, H.; Martinus, Ryan Dennis; Oback, Bjorn
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      2018 najafzadeh henderson martinus oback.pdf
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      DOI
       10.1101/397562
      Link
       www.biorxiv.org
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      Najafzadeh, V., Henderson, H., Martinus, R. D., & Oback, B. (2018). Bovine blastocyst development depends on threonine catabolism. bioRxiv. https://doi.org/10.1101/397562
      Permanent Research Commons link: https://hdl.handle.net/10289/12307
      Abstract
      Increasing evidence suggests that pluripotency is a metabolically specialised state. In mouse, inner cell mass (ICM) cells and ICM-derived pluripotent stem cells (PSCs) critically depend on catabolising the amino acid threonine, while human PSCs require leucine, lysine, methionine and tryptophan. However, little is known about the specific amino acid requirements of putative pluripotent cells in bovine. We selectively depleted candidate essential amino acids (EAAs) from individually cultured bovine embryos to study their role in blastocyst development. Depleting one (-T, -M), two (-MT, -CM, -CT, -IL, -IK, -KL) or three (-CMT, -IKL) EAAs from chemically defined protein-free culture medium did not affect the morula-to-blastocyst transition from day five (D5) to D8 in vitro. By contrast, removing six (-CIKLMT, -FHRYVW), nine (+CMT, +IKL), eleven EAAs (+T, +M) or all twelve EAAs increasingly impaired blastocyst development. As no clear candidate emerged from this targeted screen, we focussed on threonine dehydrogenase (TDH), which catalyses threonine catabolism. TDH mRNA and protein was present at similar levels in trophectoderm (TE) and ICM but absent from several adult somatic tissues. We then treated morulae with an inhibitor (Qc1) that blocks TDH from catabolising threonine. Continuous exposure to Qc1 reduced total and high-quality blastocyst development from 37% to 26% and 18% to 8%, respectively (P<0.005). This was accompanied by ~2-fold decrease in ICM, TE and total cell numbers (P<0.005), which was due to increased autophagy (P<0.05). At the same time, ICM- (NANOG) and TE-restricted (KRT8) genes were up- and down-regulated, respectively (P<0.05). In summary, bovine blastocyst viability depended on TDH-mediated threonine catabolism. However, ICM and TE cells did not metabolically differ in this regard, highlighting species-specific connections between metabolism and pluripotency regulation in mouse vs cattle.
      Date
      2018
      Type
      Journal Article
      Publisher
      Cold Spring Harbor Laboratory
      Rights
      The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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