Deletion of Neural Tube Defect-associated Gene Mthfd1l Causes Reduced Cranial Mesenchyme Density

Overview

Journal Birth Defects Res

Specialties Reproductive Medicine
Toxicology

Date 2019 Sep 14

PMID 31518072

Citations 5

Authors

Minhye Shin

Amanda Vaughn

Jessica Momb

Dean R Appling

Affiliations

Soon will be listed here.

Abstract

Background: Periconceptional intake of supplemental folic acid can reduce the incidence of neural tube defects by as much as 70%, but the mechanisms by which folic acid supports cellular processes during neural tube closure are unknown. The mitochondrial 10-formyl-tetrahydrofolate synthetase MTHFD1L catalyzes production of formate, thus generating one-carbon units for cytoplasmic processes. Deletion of Mthfd1l causes embryonic lethality, developmental delay, and neural tube defects in mice.

Methods: To investigate the role of mitochondrial one-carbon metabolism during cranial neural tube closure, we have analyzed cellular morphology and function in neural tissues in Mthfd1l knockout embryos.

Results: The head mesenchyme showed significantly lower cellular density in Mthfd1l nullizygous embryos compared to wildtype embryos during the process of neural tube closure. Apoptosis and neural crest cell specification were not affected by deletion of Mthfd1l. Sections from the cranial region of Mthfd1l knockout embryos exhibited decreased cellular proliferation, but only after completion of neural tube closure. Supplementation of pregnant dams with formate improved mesenchymal density and corrected cell proliferation in the nullizygous embryos.

Conclusions: Deletion of Mthfd1l causes decreased density in the cranial mesenchyme and this defect is improved with formate supplementation. This study reveals a mechanistic link between folate-dependent mitochondrially produced formate, head mesenchyme formation and neural tube defects.

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