Fetal neural tube stem cells from pax3 mutant mice proliferate, differentiate, and form synaptic connections when stimulated with folic acid

Shunsuke Ichi, Hiromichi Nakazaki, Vanda Boshnjaku, Ravneet Monny Singh, Barbara Mania-Farnell, Guifa Xi, David G. McLone, Tadanori Tomita, Chandra Shekhar K. Mayanil*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Although maternal intake of folic acid (FA) prevents neural tube defects in 70% of the population, the exact mechanism of prevention has not been elucidated. We hypothesized that FA affects neural stem cell (NSC) proliferation and differentiation. This hypothesis was examined in a folate-responsive spina bifida mouse model, Splotch (Sp -/-), which has a homozygous loss-of-function mutation in the Pax3 gene. Neurospheres were generated with NSCs from the lower lumbar neural tube of E10.5 wild-type (WT) and Sp -/- embryos, in the presence and absence of FA. In the absence of FA, the number of neurospheres generated from Sp -/- embryos compared with WT was minimal (P<0.05). Addition of FA to Sp -/- cultures increased the expression of a Pax3 downstream target, fgfr4, and rescued NSC proliferative potential, as demonstrated by a significant increase in neurosphere formation (P<0.01). To ascertain if FA affected cell differentiation, FA-stimulated Sp -/- neurospheres were allowed to differentiate in the continued presence or absence of FA. Neurospheres from both conditions expressed multi-potent stem cell characteristics and the same differentiation potential as WT. Further, multiple neurospheres from both WT and FA-stimulated Sp -/- cell cultures formed extensive synaptic connections. On the whole, FA-mediated rescue of neural tube defects in Sp -/- embryos promotes NSC proliferation at an early embryonic stage. FA-stimulated Sp -/- neurospheres differentiate and form synaptic connections, comparable to WT.

Original languageEnglish (US)
Pages (from-to)321-330
Number of pages10
JournalStem Cells and Development
Volume21
Issue number2
DOIs
StatePublished - Jan 20 2012

ASJC Scopus subject areas

  • Hematology
  • Developmental Biology
  • Cell Biology

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