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

in Reproduction
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  • 1 Laboratory of Reproduction and Metabolism, Universidad de Buenos Aires, Facultad de Medicina, Ciudad de Buenos Aires, Buenos Aires, Argentina
  • 2 Laboratory of Reproduction and Metabolism, CONICET-Universidad de Buenos Aires, CEFYBO, Ciudad de Buenos Aires , Buenos Aires, Argentina
  • 3 Section of Neonatology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA
  • 4 Division of Reproductive Sciences, Department of OB/GYN, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA

Correspondence should be addressed to R Higa; Email: rominahiga@gmail.com
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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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