Early methyl donor deficiency may induce persistent brain defects by reducing Stat3 signaling targeted by miR-124

Area of Science:

• Neuroscience
• Developmental Biology
• Nutritional Science

Background:

• Folate (vitamin B9) and vitamin B12 are crucial methyl donors for one-carbon metabolism, impacting epigenetic regulation.
• Low intake of these vitamins is common, posing risks for neurological and developmental disorders, especially in pregnant women and the elderly.
• Both vitamins are vital for brain development, neuroplasticity, and neuronal integrity.

Purpose of the Study:

• To investigate the effects of methyl donor deficiency (MDD) on brain development in vivo and in vitro.
• To elucidate the molecular mechanisms underlying MDD-induced brain defects, focusing on Stat3 signaling.

Main Methods:

• In utero exposure of rats to MDD and in vitro studies using hippocampal progenitor cells (H19-7).
• Analysis of Stat3 signaling pathway components (mRNA and protein levels, phosphorylation), upstream kinases, and downstream targets.
• Investigation of the role of miR-124 in regulating Stat3 and its impact on cellular phenotype.

Main Results:

• MDD caused growth retardation and long-term brain defects in specific areas.
• Decreased Stat3 levels and phosphorylation were observed in fetal brains and progenitor cells.
• MDD led to altered activity of Stat3 pathway kinases and apoptosis-related proteins (Bcl-2, Bcl-xL).
• Upregulation of miR-124 was observed under deficiency, and its silencing partially restored Stat3 signaling and improved neurite outgrowth.

Conclusions:

• Downregulation of Stat3 signaling, mediated by miR-124, is a key factor in the adverse effects of MDD on brain development.
• MDD disrupts crucial molecular pathways essential for neuronal development and integrity.
• Targeting miR-124 may offer a therapeutic strategy to mitigate the neurodevelopmental consequences of methyl donor deficiency.