title: Folate- and vitamin B12-deficient diet during gestation and lactation alters cerebellar synapsin expression via impaired influence of estrogen nuclear receptor α.
abstract: Deficiency in the methyl donors vitamin B12 and folate during pregnancy and postnatal life impairs proper brain development. We studied the consequences of this combined deficiency on cerebellum plasticity in offspring from rat mothers subjected to deficient diet during gestation and lactation and in rat neuroprogenitor cells expressing cerebellum markers. The major proteomic change in cerebellum of 21-d-old deprived females was a 2.2-fold lower expression of synapsins, which was confirmed in neuroprogenitors cultivated in the deficient condition. A pathway analysis suggested that these proteomic changes were related to estrogen receptor α (ER-α)/Src tyrosine kinase. The influence of impaired ER-α pathway was confirmed by abnormal negative geotaxis test at d 19-20 and decreased phsophorylation of synapsins in deprived females treated by ER-α antagonist 1,3-bis(4-hydroxyphenyl)-4-methyl-5-[4-(2-piperidinylethoxy)phenol]-1H-pyrazole dihydrochloride (MPP). This effect was consistent with 2-fold decreased expression and methylation of ER-α and subsequent decreased ER-α/PPAR-γ coactivator 1 α (PGC-1α) interaction in deficiency condition. The impaired ER-α pathway led to decreased expression of synapsins through 2-fold decreased EGR-1/Zif-268 transcription factor and to 1.7-fold reduced Src-dependent phosphorylation of synapsins. The treatment of neuroprogenitors with either MPP or PP1 (4-(4'-phenoxyanilino)-6,7-dimethoxyquinazoline, 6,7-dimethoxy-N-(4-phenoxyphenyl)-4-quinazolinamine, SKI-1, Src-l1) Src inhibitor produced similar effects. In conclusion, the deficiency during pregnancy and lactation impairs the expression of synapsins through a deregulation of ER-α pathway.
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy jean-louis.gueant@univ-lorraine.fr gregory.pourie@iutnb.uhp-nancy.fr.
authors.forename: Grégory
authors.initials: G
authors.lastname: Pourié
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Martin
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Carine
authors.initials: C
authors.lastname: Bossenmeyer-Pourié
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Nassila
authors.initials: N
authors.lastname: Akchiche
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Rosa Maria
authors.initials: RM
authors.lastname: Guéant-Rodriguez
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Andréa
authors.initials: A
authors.lastname: Geoffroy
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Elise
authors.initials: E
authors.lastname: Jeannesson
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Sarah
authors.initials: S
authors.lastname: El Hajj Chehadeh
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Khalid
authors.initials: K
authors.lastname: Mimoun
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Patrick
authors.initials: P
authors.lastname: Brachet
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Violette
authors.initials: V
authors.lastname: Koziel
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Alberto
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Deborah
authors.initials: D
authors.lastname: Helle
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Renée
authors.initials: R
authors.lastname: Debard
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Leininger
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Daval
authors.affiliation: *Institut National de la Santé et de la Recherche Médicale, Unité 954, Nutrition-Genetics and Environmental Exposure, Medical Faculty and University Hospital Center, Nancy University, Vandoeuvre lès Nancy, France; Human Nutrition Unit, Unité Mixte de Recherche 1019 Institut National de la Recherche Agronomique/University of Auvergne, Institut National de la Recherche Agronomique Centre of Theix, Saint-Genès Champanelle, France; and Istituto di Ricovero e Cura a Carattere Scientifico, Oasi Maria Santissima-Institute for Research on Mental Retardation and Brain Aging, Troina, Italy jean-louis.gueant@univ-lorraine.fr gregory.pourie@iutnb.uhp-nancy.fr.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
mesh_terms: D000818:Animals; D001921:Brain / Q000196:embryology / Q000378:metabolism* / Q000473:pathology; D051766:Early Growth Response Protein 1 / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005260:Female; D005494:Folic Acid Deficiency; D018507:Gene Expression Regulation, Developmental; D007774:Lactation; D058953:Neural Stem Cells / Q000378:metabolism / Q000473:pathology; D047495:PPAR gamma / Q000378:metabolism; D011247:Pregnancy; D051381:Rats; D016704:Synapsins / Q000096:biosynthesis*; D014806:Vitamin B 12 Deficiency
chemical_list: D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D047628:Estrogen Receptor alpha; D047495:PPAR gamma; D016704:Synapsins
keywords: epigenomics; methyl donor; neuroplasticity