Abstract
ABSTRACTNeural tube defects (NTDs), including spina bifida and anencephaly, are among the most common birth defects worldwide, but their underlying genetic and cellular causes are not well understood. Some NTDs are preventable by supplemental folic acid. However, despite widespread use of folic acid supplements and implementation of food fortification in many countries, the protective mechanism is unclear. Pax3 mutant (splotch; Sp2H) mice provide a model in which NTDs are preventable by folic acid and exacerbated by maternal folate deficiency. Here, we found that cell proliferation was diminished in the dorsal neuroepithelium of mutant embryos, corresponding to the region of abolished Pax3 function. This was accompanied by premature neuronal differentiation in the prospective midbrain. Contrary to previous reports, we did not find evidence that increased apoptosis could underlie failed neural tube closure in Pax3 mutant embryos, nor that inhibition of apoptosis could prevent NTDs. These findings suggest that Pax3 functions to maintain the neuroepithelium in a proliferative, undifferentiated state, allowing neurulation to proceed. NTDs in Pax3 mutants were not associated with abnormal abundance of specific folates and were not prevented by formate, a one-carbon donor to folate metabolism. Supplemental folic acid restored proliferation in the cranial neuroepithelium. This effect was mediated by enhanced progression of the cell cycle from S to G2 phase, specifically in the Pax3 mutant dorsal neuroepithelium. We propose that the cell-cycle-promoting effect of folic acid compensates for the loss of Pax3 and thereby prevents cranial NTDs.
Highlights
Neural tube defects (NTDs) such as anencephaly and spina bifida are among the most common birth defects worldwide, affecting more than 250,000 pregnancies every year (Copp et al, 2013; Zaganjor et al, 2016)
NTDs in Pax3 (Sp2H) mutant embryos do not result from excess apoptosis NTDs in splotch embryos result from a cell-autonomous defect in the neuroepithelium (Goulding et al, 1991; Li et al, 1999)
If excess apoptosis is the cause of cranial NTDs in Pax3 mutants, this should be detectable prior to and/or during closure of the cranial neuroepithelium, which has not previously been examined
Summary
Neural tube defects (NTDs) such as anencephaly and spina bifida are among the most common birth defects worldwide, affecting more than 250,000 pregnancies every year (Copp et al, 2013; Zaganjor et al, 2016). Maternal use of supplemental folic acid (FA) prevents a proportion of NTDs (Berry et al, 1999; Czeizel and Dudás, 1992; MRC Vitamin Study Research Group, 1991), and FA. §Present address: Department of Health Sciences, University of Milan, Italy. Developmental Biology and Cancer Research and Teaching Department, UCL Great Ormond Street Institute of Child Health, University College London, London WC1N 1EH, UK. FA is converted via dihydrofolate to THF, with subsequent addition of 1C groups derived principally from serine, glycine and formate (Tibbetts and Appling, 2010; Leung et al, 2017)
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