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

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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.

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Acknowledgments

The authors wish to thank Bill Goossens, Microscope facility at Lurie Children’s Hospital of Chicago Research Center. This work was supported by the State of Illinois Excellence in Academic Medicine award (to CSM), a Grant from the Spastic Paralysis Research Foundation of Illinois-Eastern Iowa District of Kiwanis (to CSM and DGM), and the Spina Bifida Association and Ann and Robert H. Lurie Children’s Hospital of Chicago Research Center Pilot Grant award (to CSM), and Eleanor Clarke Distinguished Developmental Neurobiology Research Scholar endowment (CSM) and in part by NIH grant HD067244 (RHF).

Conflict of interest

We declare no conflict of interests.

Author information

Author notes

  1. Takao Tsurubuchi

    Present address: Department of Neurosurgery, Graduate School of Comprehensive Human Sciences, University of Tsukuba, Tsukuba, Ibaraki, Japan

  2. Vanda Boshnjaku

    Present address: American University of Antigua College of Medicine, Jabberwock Beach Road, Coolidge, Antigua

Authors and Affiliations

  1. 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

    Takao Tsurubuchi, Elise V. Allender, M. Rizwan Siddiqui, Kyu-Won Shim, Shunsuke Ichi, Vanda Boshnjaku, Guifa Xi, David G. McLone, Tadanori Tomita & C. S. Mayanil

  2. Department of Pediatric Neurosurgery, Severance Children’s Hospital, Yonsei University College of Medicine, Seoul, South Korea

    Kyu-Won Shim

  3. Department of Neurosurgery, Japanese Red Cross Medical Center, 4-1-22, Hiroo, Shibuya, Tokyo, 150-8935, Japan

    Shunsuke Ichi

  4. Department of Biology, Purdue University Calumet, Hammond, IN, 46323, USA

    Barbara Mania-Farnell

  5. Dell Pediatric Research Institute, The University of Texas at Austin, Austin, TX, 78723, USA

    Richard H. Finnell

Authors
  1. Takao Tsurubuchi
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  2. Elise V. Allender
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  8. Guifa Xi
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  9. Richard H. Finnell
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  10. David G. McLone
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Corresponding authors

Correspondence to Tadanori Tomita or C. S. Mayanil.

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Tsurubuchi, T., Allender, E.V., Siddiqui, M.R. et al. A critical role of noggin in developing folate-nonresponsive NTD in Fkbp8 −/− embryos. Childs Nerv Syst 30, 1343–1353 (2014). https://doi.org/10.1007/s00381-014-2428-1

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  • DOI: https://doi.org/10.1007/s00381-014-2428-1

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