Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy

Abstract Oxidative stress constitutes a major cause for increased risk of congenital malformations associated to severe hyperglycaemia during pregnancy. Mutations in the gene encoding the transcription factor ALX3 cause congenital craniofacial and neural tube defects. Since oxidative stress and lack...

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Autores principales:	Patricia García-Sanz, Mercedes Mirasierra, Rosario Moratalla, Mario Vallejo
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2017
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/4d468524762b464b86e230b22717eda6
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spelling	oai:doaj.org-article:4d468524762b464b86e230b22717eda62021-12-02T15:06:06ZEmbryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy10.1038/s41598-017-00334-12045-2322https://doaj.org/article/4d468524762b464b86e230b22717eda62017-03-01T00:00:00Zhttps://doi.org/10.1038/s41598-017-00334-1https://doaj.org/toc/2045-2322Abstract Oxidative stress constitutes a major cause for increased risk of congenital malformations associated to severe hyperglycaemia during pregnancy. Mutations in the gene encoding the transcription factor ALX3 cause congenital craniofacial and neural tube defects. Since oxidative stress and lack of ALX3 favour excessive embryonic apoptosis, we investigated whether ALX3-deficiency further increases the risk of embryonic damage during gestational hyperglycaemia in mice. We found that congenital malformations associated to ALX3-deficiency are enhanced in diabetic pregnancies. Increased expression of genes encoding oxidative stress-scavenging enzymes in embryos from diabetic mothers was blunted in the absence of ALX3, leading to increased oxidative stress. Levels of ALX3 increased in response to glucose, but ALX3 did not activate oxidative stress defence genes directly. Instead, ALX3 stimulated the transcription of Foxo1, a master regulator of oxidative stress-scavenging genes, by binding to a newly identified binding site located in the Foxo1 promoter. Our data identify ALX3 as an important component of the defence mechanisms against the occurrence of developmental malformations during diabetic gestations, stimulating the expression of oxidative stress-scavenging genes in a glucose-dependent manner via Foxo1 activation. Thus, ALX3 deficiency provides a novel molecular mechanism for developmental defects arising from maternal hyperglycaemia.Patricia García-SanzMercedes MirasierraRosario MoratallaMario VallejoNature 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 Patricia García-Sanz Mercedes Mirasierra Rosario Moratalla Mario Vallejo Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy
description	Abstract Oxidative stress constitutes a major cause for increased risk of congenital malformations associated to severe hyperglycaemia during pregnancy. Mutations in the gene encoding the transcription factor ALX3 cause congenital craniofacial and neural tube defects. Since oxidative stress and lack of ALX3 favour excessive embryonic apoptosis, we investigated whether ALX3-deficiency further increases the risk of embryonic damage during gestational hyperglycaemia in mice. We found that congenital malformations associated to ALX3-deficiency are enhanced in diabetic pregnancies. Increased expression of genes encoding oxidative stress-scavenging enzymes in embryos from diabetic mothers was blunted in the absence of ALX3, leading to increased oxidative stress. Levels of ALX3 increased in response to glucose, but ALX3 did not activate oxidative stress defence genes directly. Instead, ALX3 stimulated the transcription of Foxo1, a master regulator of oxidative stress-scavenging genes, by binding to a newly identified binding site located in the Foxo1 promoter. Our data identify ALX3 as an important component of the defence mechanisms against the occurrence of developmental malformations during diabetic gestations, stimulating the expression of oxidative stress-scavenging genes in a glucose-dependent manner via Foxo1 activation. Thus, ALX3 deficiency provides a novel molecular mechanism for developmental defects arising from maternal hyperglycaemia.
format	article
author	Patricia García-Sanz Mercedes Mirasierra Rosario Moratalla Mario Vallejo
author_facet	Patricia García-Sanz Mercedes Mirasierra Rosario Moratalla Mario Vallejo
author_sort	Patricia García-Sanz
title	Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy
title_short	Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy
title_full	Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy
title_fullStr	Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy
title_full_unstemmed	Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy
title_sort	embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of alx3 to prevent malformations during diabetic pregnancy
publisher	Nature Portfolio
publishDate	2017
url	https://doaj.org/article/4d468524762b464b86e230b22717eda6
work_keys_str_mv	AT patriciagarciasanz embryonicdefencemechanismsagainstglucosedependentoxidativestressrequireenhancedexpressionofalx3topreventmalformationsduringdiabeticpregnancy AT mercedesmirasierra embryonicdefencemechanismsagainstglucosedependentoxidativestressrequireenhancedexpressionofalx3topreventmalformationsduringdiabeticpregnancy AT rosariomoratalla embryonicdefencemechanismsagainstglucosedependentoxidativestressrequireenhancedexpressionofalx3topreventmalformationsduringdiabeticpregnancy AT mariovallejo embryonicdefencemechanismsagainstglucosedependentoxidativestressrequireenhancedexpressionofalx3topreventmalformationsduringdiabeticpregnancy
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Embryonic defence mechanisms against glucose-dependent oxidative stress require enhanced expression of Alx3 to prevent malformations during diabetic pregnancy

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