Inhibition of MTOR signaling impairs rat embryo organogenesis by affecting folate availability

in Reproduction
Authors:
Romina Higa Laboratory of Reproduction and Metabolism, Universidad de Buenos Aires, Facultad de Medicina, Ciudad de Buenos Aires, Buenos Aires, Argentina
Laboratory of Reproduction and Metabolism, CONICET-Universidad de Buenos Aires, CEFYBO, Ciudad de Buenos Aires , Buenos Aires, Argentina

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https://orcid.org/0000-0001-7397-8868
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Fredrick J Rosario Division of Reproductive Sciences, Department of OB/GYN, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Theresa L Powell Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
Division of Reproductive Sciences, Department of OB/GYN, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Thomas Jansson Division of Reproductive Sciences, Department of OB/GYN, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

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Alicia Jawerbaum Laboratory of Reproduction and Metabolism, Universidad de Buenos Aires, Facultad de Medicina, Ciudad de Buenos Aires, Buenos Aires, Argentina
Laboratory of Reproduction and Metabolism, CONICET-Universidad de Buenos Aires, CEFYBO, Ciudad de Buenos Aires , Buenos Aires, Argentina

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Correspondence should be addressed to R Higa; Email: rominahiga@gmail.com
DOI:
https://doi.org/10.1530/REP-20-0603
Volume/Issue:
Volume 161: Issue 4
Page Range:
365–373
Article Type:
Research Article
Online Publication Date:
Apr 2021
Copyright:
© 2021 Society for Reproduction and Fertility 2021
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Mechanistic target of rapamycin (MTOR) is essential for embryo development by acting as a nutrient sensor to regulate cell growth, proliferation and metabolism. Folate is required for normal embryonic development and it was recently reported that MTOR functions as a folate sensor. In this work, we tested the hypothesis that MTOR functions as a folate sensor in the embryo and its inhibition result in embryonic developmental delay affecting neural tube closure and that these effects can be rescued by folate supplementation. Administration of rapamycin (0.5 mg/kg) to rats during early organogenesis inhibited embryonic ribosomal protein S6, a downstream target of MTOR Complex1, markedly reduced embryonic folate incorporation (−84%, P < 0.01) and induced embryo developmental impairments, as shown by an increased resorption rate, reduced embryo somite number and delayed neural tube closure. These alterations were prevented by folic acid administered to the dams. Differently, although an increased rate of embryonic rotation defects was observed in the rapamycin-treated dams, this alteration was not prevented by maternal folic acid supplementation. In conclusion, MTOR inhibition during organogenesis in the rat resulted in decreased folate levels in the embryo, increased embryo resorption rate and impaired embryo development. These data suggest that MTOR signaling influences embryo folate availability, possibly by regulating the transfer of folate across the maternal–embryonic interface.

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Print ISSN:
1470-1626
Online ISSN:
1741-7899

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