Folic acid supplementation can adversely affect murine neural tube closure and embryonic survival

Abstract

Neural tube defects (NTDs), a common birth defect in humans, result from the failure of the embryonic neural tube (NT) to close properly. NT closure is a complex, poorly understood morphogenetic process influenced by genes and environment. The most effective environmental influence in decreasing the risk for NTDs is folic acid (FA) fortification and supplementation, and these findings led to the recommendation of periconceptual FA intake and mandatory fortification of the US grain supply in 1998. To explore the relationship between genetics and responsiveness to FA supplementation, we used five mouse NTDs models-Zic2, Shroom3, Frem2, Grhl2 (Grainyhead-like 2) and L3P (Line3P)-and a long-term generational FA supplementation scheme. Contrary to expectations, we find that three genetic mutants respond adversely to FA supplementation with increased incidence of NTDs in homozygous mutants, occurrence of NTDs in heterozygous embryos and embryonic lethality prior to NT closure. Because of these unexpected responses, we examined NTD risk after short-term FA supplementation. Our results indicate that, for the same genetic allele, NTD risk can depend on the length of FA exposure. Our data indicate that, depending on the gene mutation, FA supplementation may adversely influence embryonic development and NT closure.

p120-catenin-dependent junctional recruitment of Shroom3 is required for apical constriction during lens pit morphogenesis

“…To block Rock binding to Shroom3, a single missense ) that lies within a short critical sequence known to associate with Rock1 (Mohan et al, 2012). Furthermore, this exact same missense mutation causes severe morphogenetic defects that are similar to those found in mice with a germline deletion of Shroom3 (Marean et al, 2011;Massarwa and Niswander, 2013). When Shroom3 R1838C was expressed in A431D cells that express N-cadherin wt , it was effectively recruited to the junctions (Fig.…”

Folate and Prevention of Neural Tube Disease

“…Therefore several reports support the hypothesis that folic acid likely acts through diverse mechanisms to influence neural tube closure (Li et al, 2011;Marean et al, 2011) so in future it will be of interest to determine the mechanistic basis of the specific gene-environment interactions that together influence neural tube closure.…”

“…Moreover, mouse NTD models have the potential to aid in understanding the genetics underlying folic acid responsiveness or nonresponsiveness in NTD prevention (Harris, 2009). Recently Marean et al, 2011 suggested that the response to folic acid supplementation may be more complex. They report that depending on the gene mutation, folic acid supplementation may adversely influence embryonic development and neural tube closure and thus the genetics of an individual may determine whether FA provides a beneficial outcome.…”

“…The dose of folic acid, either alone or as part of a multivitamin preparation, varied between 400 to 5000 μg (0.4-5 mg) per day and was taken at least 1 month before conception and throughout the first trimester. In some countries, such as the and survivors face life-long morbidities including neurologic, cognitive, urologic, and gastrointestinal complications (Marean et al, 2011). NTDs are devastating conditions as most of the lesions are always associated with neurological deficits producing varying degree of limb paresis/paralysis, bladder and anorectal incontinence (Digra, 2004).…”

Neural development and regeneration: it's all in your spinal cord

“…wikispaces.com/). Her work has also addressed the influence of environmental factors, unexpectedly revealing that folic acid supplements in NTD mouse mutants can worsen their defects (Marean et al, 2011). This raises questions about the general recommendation of folic acid supplementation during pregnancy.…”