A critical role of noggin in developing folate-nonresponsive NTD in Fkbp8-/- embryos

Takao Tsurubuchi, Elise V. Allender, M. Rizwan Siddiqui, Kyu Won Shim, Shunsuke Ichi, Vanda Boshnjaku, Barbara Mania-Farnell, Guifa Xi, Richard H. Finnell, David G. McLone, Tadanori Tomita*, C. S. Mayanil

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

Purpose: 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.

Original languageEnglish (US)
Pages (from-to)1343-1353
Number of pages11
JournalChild's Nervous System
Volume30
Issue number8
DOIs
StatePublished - Aug 2014

Keywords

  • H3K27me3
  • Msx2
  • Neural stem cell
  • Noggin
  • Olig2
  • UTX

ASJC Scopus subject areas

  • Pediatrics, Perinatology, and Child Health
  • Clinical Neurology

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