title: Occurrence of cleft-palate and alteration of Tgf-β(3) expression and the mechanisms leading to palatal fusion in mice following dietary folic-acid deficiency.
abstract: Folic acid (FA) is essential for numerous bodily functions. Its decrease during pregnancy has been associated with an increased risk of congenital malformations in the progeny. The relationship between FA deficiency and the appearance of cleft palate (CP) is controversial, and little information exists on a possible effect of FA on palate development. We investigated the effect of a 2-8 weeks' induced FA deficiency in female mice on the development of CP in their progeny as well as the mechanisms leading to palatal fusion, i.e. cell proliferation, cell death, and palatal-shelf adhesion and fusion. We showed that an 8 weeks' maternal FA deficiency caused complete CP in the fetuses although a 2 weeks' maternal FA deficiency was enough to alter all the mechanisms analyzed. Since transforming growth factor-β(3) (TGF-β(3)) is crucial for palatal fusion and since most of the mechanisms impaired by FA deficiency were also observed in the palates of Tgf-β(3)null mutant mice, we investigated the presence of TGF-β(3) mRNA, its protein and phospho-SMAD2 in FA-deficient (FAD) mouse palates. Our results evidenced a large reduction in Tgf-β(3) expression in palates of embryos of dams fed an FAD diet for 8 weeks; Tgf-β(3) expression was less reduced in palates of embryos of dams fed an FAD diet for 2 weeks. Addition of TGF-β(3) to palatal-shelf cultures of embryos of dams fed an FAD diet for 2 weeks normalized all the altered mechanisms. Thus, an insufficient folate status may be a risk factor for the development of CP in mice, and exogenous TGF-β(3) compensates this deficit in vitro.
authors.affiliation: Departamento de Anatomía y Embriología Humana I, Facultad de Odontología, Universidad Complutense, Madrid, Spain.
authors.forename: Estela
authors.initials: E
authors.lastname: Maldonado
authors.forename: Jorge
authors.initials: J
authors.lastname: Murillo
authors.forename: Carmen
authors.initials: C
authors.lastname: Barrio
authors.forename: Aurora
authors.initials: A
authors.lastname: del Río
authors.forename: Juliana
authors.initials: J
authors.lastname: Pérez-Miguelsanz
authors.forename: Yamila
authors.initials: Y
authors.lastname: López-Gordillo
authors.forename: Teresa
authors.initials: T
authors.lastname: Partearroyo
authors.forename: Irene
authors.initials: I
authors.lastname: Paradas
authors.forename: Carmen
authors.initials: C
authors.lastname: Maestro
authors.forename: Elena
authors.initials: E
authors.lastname: Martínez-Sanz
authors.forename: Gregorio
authors.initials: G
authors.lastname: Varela-Moreiras
authors.forename: Concepción
authors.initials: C
authors.lastname: Martínez-Álvarez
mesh_terms: D000818:Animals; D002972:Cleft Palate / Q000209:etiology* / Q000235:genetics* / Q000473:pathology; D005260:Female; D005492:Folic Acid / Q000378:metabolism; D005494:Folic Acid Deficiency / Q000150:complications*; D018507:Gene Expression Regulation, Developmental; D051379:Mice; D008810:Mice, Inbred C57BL; D010159:Palate / Q000378:metabolism / Q000473:pathology; D011247:Pregnancy; D012333:RNA, Messenger / Q000235:genetics; D012307:Risk Factors; D053782:Transforming Growth Factor beta3 / Q000235:genetics*
chemical_list: D012333:RNA, Messenger; D053782:Transforming Growth Factor beta3; D005492:Folic Acid