Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice

Abstract Maternal folate deficiency is linked to restricted fetal growth, however the underlying mechanisms remain to be established. Here we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and amino a...

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Autores principales:	Fredrick J. Rosario, Peter W. Nathanielsz, Theresa L. Powell, Thomas Jansson
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/281d91b210924359b1352bbc4d3da318
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spelling	oai:doaj.org-article:281d91b210924359b1352bbc4d3da3182021-12-02T16:07:48ZMaternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice10.1038/s41598-017-03888-22045-2322https://doaj.org/article/281d91b210924359b1352bbc4d3da3182017-06-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-03888-2https://doaj.org/toc/2045-2322Abstract Maternal folate deficiency is linked to restricted fetal growth, however the underlying mechanisms remain to be established. Here we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and amino acid transporter activity and causes fetal growth restriction. Folate deficient mice had lower serum folate (−60%). In late pregnancy, fetal weight in the folate deficient group was decreased (−17%, p < 0.05), whereas placental weight, litter size and crown rump length were unaltered. Maternal folate deficiency inhibited placental mTORC1 and mTORC2 signaling and decreased trophoblast plasma membrane System A and L amino acid transporter activities and transporter isoform expression. Folate deficiency also caused a decrease in phosphorylation of specific functional readouts of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues. We have identified a novel specific molecular link between maternal folate availability and fetal growth, involving regulation of placental mTOR signaling by folate, resulting in changes in placental nutrient transport. mTOR folate sensing may have broad biological significance because of the critical role of folate in normal cell function and the wide range of disorders, including cancer, that have been linked to folate availability.Fredrick J. RosarioPeter W. NathanielszTheresa L. PowellThomas JanssonNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 7, Iss 1, Pp 1-15 (2017)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Fredrick J. Rosario Peter W. Nathanielsz Theresa L. Powell Thomas Jansson Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice
description	Abstract Maternal folate deficiency is linked to restricted fetal growth, however the underlying mechanisms remain to be established. Here we tested the hypothesis that mTOR functions as a folate sensor in vivo in mice and that maternal folate deficiency inhibits placental mTOR signaling and amino acid transporter activity and causes fetal growth restriction. Folate deficient mice had lower serum folate (−60%). In late pregnancy, fetal weight in the folate deficient group was decreased (−17%, p < 0.05), whereas placental weight, litter size and crown rump length were unaltered. Maternal folate deficiency inhibited placental mTORC1 and mTORC2 signaling and decreased trophoblast plasma membrane System A and L amino acid transporter activities and transporter isoform expression. Folate deficiency also caused a decrease in phosphorylation of specific functional readouts of mTORC1 and mTORC2 signaling in multiple maternal and fetal tissues. We have identified a novel specific molecular link between maternal folate availability and fetal growth, involving regulation of placental mTOR signaling by folate, resulting in changes in placental nutrient transport. mTOR folate sensing may have broad biological significance because of the critical role of folate in normal cell function and the wide range of disorders, including cancer, that have been linked to folate availability.
format	article
author	Fredrick J. Rosario Peter W. Nathanielsz Theresa L. Powell Thomas Jansson
author_facet	Fredrick J. Rosario Peter W. Nathanielsz Theresa L. Powell Thomas Jansson
author_sort	Fredrick J. Rosario
title	Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice
title_short	Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice
title_full	Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice
title_fullStr	Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice
title_full_unstemmed	Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice
title_sort	maternal folate deficiency causes inhibition of mtor signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/281d91b210924359b1352bbc4d3da318
work_keys_str_mv	AT fredrickjrosario maternalfolatedeficiencycausesinhibitionofmtorsignalingdownregulationofplacentalaminoacidtransportersandfetalgrowthrestrictioninmice AT peterwnathanielsz maternalfolatedeficiencycausesinhibitionofmtorsignalingdownregulationofplacentalaminoacidtransportersandfetalgrowthrestrictioninmice AT theresalpowell maternalfolatedeficiencycausesinhibitionofmtorsignalingdownregulationofplacentalaminoacidtransportersandfetalgrowthrestrictioninmice AT thomasjansson maternalfolatedeficiencycausesinhibitionofmtorsignalingdownregulationofplacentalaminoacidtransportersandfetalgrowthrestrictioninmice
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Maternal folate deficiency causes inhibition of mTOR signaling, down-regulation of placental amino acid transporters and fetal growth restriction in mice

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