The effect of folic acid deficiency on FGF pathwayviaBrachyury regulation in neural tube defects

Abstract

Folate deficiency in early development leads to disturbance in multiple processes, including neurogenesis during which fibroblast growth factor (FGF) pathway is one of the crucial pathways. Whether folic acid (FA) directly affects FGF pathways to influence neurodevelopment and the possible mechanism remains unclear. In this study, we presented evidence that in human FA‐insufficient encephalocele, the FGF pathway was interfered. Furthermore, in Brachyury knockout mice devoid of such T‐box transcription factors regulating embryonic neuromesodermal bipotency and a key component of FGF pathway, change in expression of Brachyury downstream targets, activator Fgf8 and suppressor dual specificity phosphatase 6 was detected, along with the reduction in expression of other key FGF pathway genes. By using a FA‐deficient cell model, we further demonstrated that decrease in Brachyury expression was through alteration in hypermethylation at the Brachyury promoter region under FA deficiency conditions, and suppression of Brachyury promoted the inactivation of the FGF pathway. Correspondingly, FA supplementation partially reverses the effects seen in FA‐deficient embryoid bodies. Lastly, in mice with maternal folate‐deficient diets, aberrant FGF pathway activity was found in fetal brain dysplasia. Taken together, our findings highlight the effect of FA on FGF pathways during neurogenesis, and the mechanism may be due to the low expression of Brachyury gene via hypermethylation under FA‐insufficient conditions.—Chang, S., Lu, X., Wang, S., Wang, Z., Huo, J., Huang, J., Shangguan, S., Li, S., Zou, J., Bao, Y., Guo, J., Wang, F., Niu, B., Zhang, T., Qiu, Z., Wu, J., Wang, L. The effect of folic acid deficiency on FGF pathway via Brachyury regulation in neural tube defects. FASEB J. 33, 4688–4702 (2019). http://www.fasebj.org

The association between diverse serum folate with MAFLD and liver fibrosis based on NHANES 2017–2020

“…Furthermore, inadequate folate levels may disrupt the fibroblast growth factor (FGF) pathways. FGF concentrations have been correlated with insulin resistance, and the regulation of visceral adiposity, by FGF stimulates adipokines and inflammatory factors, thereby fostering the progression of lipotoxic liver disease ( 27 , 28 ). Thirdly, folate exerts regulatory control over the transcription of NADPH oxidase, effectively mitigating the oxidative stress induced by a high-fat diet ( 29 ).…”

Embryology of the Abdominal Wall and Associated Malformations—A Review

“…Primary neurulation is initiated at the neural plate, a condensation of specialized ectodermal cells, and starts around day 19 after fertilization. The plate undergoes fundamental transformations of shape ( Figure 2 ), cell morphology and size, during which the neural plate bends, the prerequisite for forming neural folds ( 32 , 34 ).Furthermore Chang et al demonstrated in Brachyury knock out mice that folic acid deficiency interferes neural induction via inactivation of the FGF pathway ( 35 ).…”

Debris-stimulated tumor growth: a Pandora’s box?

“…In the subthreshold inoculum model, instead of suppressing tumor growth, chemotherapy promoted tumor growth in small or dormant tumors via tumor-promoting debris [ 1 , 3 ]. Similarly, chemotherapy-generated tumor cell “debris” (apoptotic and necrotic cells and cell fragments) promotes cancer progression and metastasis via stimulating an eicosanoid-driven cytokine storm of pro-inflammatory and pro-angiogenic mediators [ 1 , 2 , 14 , 38 , 39 , 57 , 76 ], polarizing tumor-associated macrophages (TAMs) as well as inducing immunosuppression and limiting anti-tumor immunity [ 24 , 77 , 78 ]. Thus, new approaches to stimulate the clearance of tumor cell debris are urgently needed [ 1 , 21 , 40 , 78 – 80 ].…”