title: A critical role of noggin in developing folate-nonresponsive NTD in Fkbp8 -/- embryos.
abstract: OBJECTIVE
  Maternal folate intake has reduced the incidence of human neural tube defects by 60-70 %. However, 30-40 % of cases remain nonresponsive to folate intake. The main purpose of this study was to understand the molecular mechanism of folate nonresponsiveness in a mouse model of neural tube defect.
  
  
  METHODS
  We used a folate-nonresponsive Fkbp8 knockout mouse model to elucidate the molecular mechanism(s) of folate nonresponsiveness. Neurospheres were grown from neural stem cells isolated from the lumbar neural tube of E9.5 Fkbp8 (-/-) and wild-type embryos. Immunostaining was used to determine the protein levels of oligodendrocyte transcription factor 2 (Olig2), Nkx6.1, class III beta-tubulin (TuJ1), O4, glial fibrillary acidic protein (GFAP), histone H3 Lys27 trimethylation (H3K27me3), ubiquitously transcribed tetratricopeptide repeat (UTX), and Msx2, and quantitative real-time (RT)-PCR was used to determine the message levels of Olig2, Nkx6.1, Msx2, and noggin in neural stem cells differentiated in the presence and absence of folic acid.
  
  
  RESULTS
  Fkbp8 (-/-)-derived neural stem cells showed (i) increased noggin expression; (ii) decreased Msx2 expression; (iii) premature differentiation--neurogenesis, oligodendrogenesis (Olig2 expression), and gliogenesis (GFAP expression); and (iv) increased UTX expression and decreased H3K27me3 polycomb modification. Exogenous folic acid did not reverse these markers.
  
  
  CONCLUSIONS
  Folate nonresponsiveness could be attributed in part to increased noggin expression in Fkbp8 (-/-) embryos, resulting in decreased Msx2 expression. Folate treatment further increases Olig2 and noggin expression, thereby exacerbating ventralization.
authors.affiliation: Developmental Neurobiology Laboratory, Department of Pediatric Neurosurgery, Developmental Biology Program, Lurie Children's Research Center, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL, 60614, USA.
authors.forename: Takao
authors.initials: T
authors.lastname: Tsurubuchi
authors.forename: Elise V
authors.initials: EV
authors.lastname: Allender
authors.forename: M Rizwan
authors.initials: MR
authors.lastname: Siddiqui
authors.forename: Kyu-Won
authors.initials: KW
authors.lastname: Shim
authors.forename: Shunsuke
authors.initials: S
authors.lastname: Ichi
authors.forename: Vanda
authors.initials: V
authors.lastname: Boshnjaku
authors.forename: Barbara
authors.initials: B
authors.lastname: Mania-Farnell
authors.forename: Guifa
authors.initials: G
authors.lastname: Xi
authors.forename: Richard H
authors.initials: RH
authors.lastname: Finnell
authors.forename: David G
authors.initials: DG
authors.lastname: McLone
authors.forename: Tadanori
authors.initials: T
authors.lastname: Tomita
authors.forename: C S
authors.initials: CS
authors.lastname: Mayanil
mesh_terms: D000818:Animals; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004622:Embryo, Mammalian; D005260:Female; D005492:Folic Acid / Q000009:adverse effects*; D018507:Gene Expression Regulation, Developmental / Q000187:drug effects / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058953:Neural Stem Cells / Q000187:drug effects / Q000378:metabolism; D009436:Neural Tube Defects / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism; D011247:Pregnancy; D022021:Tacrolimus Binding Proteins / Q000172:deficiency* / Q000235:genetics; D000099176:Noggin Protein
chemical_list: D002352:Carrier Proteins; D005492:Folic Acid; D018398:Homeodomain Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; D022021:Tacrolimus Binding Proteins; D000099176:Noggin Protein; C119437:Fkbp8 protein, mouse; C084119:MSX2 protein; C523761:Kdm6b protein, mouse