title: Late Maternal Folate Supplementation Rescues from Methyl Donor Deficiency-Associated Brain Defects by Restoring Let-7 and miR-34 Pathways.
abstract: The micronutrients folate and vitamin B12 are essential for the proper development of the central nervous system, and their deficiency during pregnancy has been associated with a wide range of disorders. They act as methyl donors in the one-carbon metabolism which critically influences epigenetic mechanisms. In order to depict further underlying mechanisms, we investigated the role of let-7 and miR-34, two microRNAs regulated by methylation, on a rat model of maternal deficiency. In several countries, public health policies recommend periconceptional supplementation with folic acid. However, the question about the duration and periodicity of supplementation remains. We therefore tested maternal supply (3 mg/kg/day) during the last third of gestation from embryonic days (E) 13 to 20. Methyl donor deficiency-related developmental disorders at E20, including cerebellar and interhemispheric suture defects and atrophy of selective cerebral layers, were associated with increased brain expression (by 2.5-fold) of let-7a and miR-34a, with subsequent downregulation of their regulatory targets such as Trim71 and Notch signaling partners, respectively. These processes could be reversed by siRNA strategy in differentiating neuroprogenitors lacking folate, with improvement of their morphological characteristics. While folic acid supplementation helped restoring the levels of let-7a and miR-34a and their downstream targets, it led to a reduction of structural and functional defects taking place during the perinatal period. Our data outline the potential role of let-7 and miR-34 and their related signaling pathways in the developmental defects following gestational methyl donor deficiency and support the likely usefulness of late folate supplementation in at risk women.
authors.affiliation: Inserm U954, 9 Avenue de la Forêt de Haye, 54500, Vandoeuvre-lès-Nancy, France.|Faculté de Médecine de Nancy, Université de Lorraine, 54500, Vandoeuvre-lès-Nancy, France.
authors.forename: Andréa
authors.initials: A
authors.lastname: Geoffroy
authors.affiliation: Inserm U954, 9 Avenue de la Forêt de Haye, 54500, Vandoeuvre-lès-Nancy, France.|Faculté de Médecine de Nancy, Université de Lorraine, 54500, Vandoeuvre-lès-Nancy, France.
authors.forename: Racha
authors.initials: R
authors.lastname: Kerek
authors.affiliation: Inserm U954, 9 Avenue de la Forêt de Haye, 54500, Vandoeuvre-lès-Nancy, France.|Faculté de Médecine de Nancy, Université de Lorraine, 54500, Vandoeuvre-lès-Nancy, France.
authors.forename: Grégory
authors.initials: G
authors.lastname: Pourié
authors.affiliation: Inserm U954, 9 Avenue de la Forêt de Haye, 54500, Vandoeuvre-lès-Nancy, France.|Faculté de Médecine de Nancy, Université de Lorraine, 54500, Vandoeuvre-lès-Nancy, France.
authors.forename: Déborah
authors.initials: D
authors.lastname: Helle
authors.affiliation: Inserm U954, 9 Avenue de la Forêt de Haye, 54500, Vandoeuvre-lès-Nancy, France.|Faculté de Médecine de Nancy, Université de Lorraine, 54500, Vandoeuvre-lès-Nancy, France.|IRCCS, Oasi Maria S.S., Institute for Research on Mental Retardation and Brain Aging, 94018, Troina, EN, Italy.
authors.forename: Jean-Louis
authors.initials: JL
authors.lastname: Guéant
authors.affiliation: Inserm U954, 9 Avenue de la Forêt de Haye, 54500, Vandoeuvre-lès-Nancy, France. jean-luc.daval@inserm.fr.|Faculté de Médecine de Nancy, Université de Lorraine, 54500, Vandoeuvre-lès-Nancy, France. jean-luc.daval@inserm.fr.
authors.forename: Jean-Luc
authors.initials: JL
authors.lastname: Daval
authors.affiliation: Inserm U954, 9 Avenue de la Forêt de Haye, 54500, Vandoeuvre-lès-Nancy, France. carine.pourie@univ-lorraine.fr.|Faculté de Médecine de Nancy, Université de Lorraine, 54500, Vandoeuvre-lès-Nancy, France. carine.pourie@univ-lorraine.fr.
authors.forename: Carine
authors.initials: C
authors.lastname: Bossenmeyer-Pourié
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism*; D001927:Brain Diseases / Q000188:drug therapy* / Q000196:embryology / Q000235:genetics; D019587:Dietary Supplements; D005260:Female; D005492:Folic Acid / Q000494:pharmacology*; D035683:MicroRNAs / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D011247:Pregnancy; D017208:Rats, Wistar
chemical_list: C560944:MIRN34 microRNA, rat; C548145:MIRNLET7 microRNA, rat; D035683:MicroRNAs; D005492:Folic Acid
keywords: Belated folate supplementation; Brain development; Epigenetics; Folate; Vitamin B12; microRNAs