Pathogenesis of neural tube defects: The regulation and disruption of cellular processes underlying neural tube closure

Abstract

Neural tube closure (NTC) is crucial for proper development of the brain and spinal cord and requires precise morphogenesis from a sheet of cells to an intact three-dimensional structure. NTC is dependent on successful regulation of hundreds of genes, a myriad of signaling pathways, concentration gradients, and is influenced by epigenetic and environmental cues. Failure of NTC is termed a neural tube defect (NTD) and is a leading class of congenital defects in the United States and worldwide. Though NTDs are all defined as incomplete closure of the neural tube, the pathogenesis of an NTD determines the type, severity, positioning, and accompanying phenotypes. In this review, we survey pathogenesis of NTDs relating to disruption of cellular processes arising from genetic mutations, altered epigenetic regulation, and environmental influences by micronutrients and maternal condition. This article is categorized under: Congenital Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Genetics/Genomics/Epigenetics Neurological Diseases > Stem Cells and Development.

Keywords: environmental factors; epigenetics; folic acid; neural tube defect; neurulation; pathogenesis.

Figure 1:. NTD phenotypes

A) Human anencephaly B) Mouse exencephaly C) Human spina bifida D) Mouse spina bifida Fig 1A,C from Wilde, 2014

Figure 2:. Process of NTC

A) NTC begins with a flat sheet of epithelial cells (NE cells shown in green, NNE cells shown in blue) overlaying the notochord (yellow) and mesoderm (pink). B) Convergent extension and proliferation drive the bulging of the mesoderm and formation of neural folds. C) Actomyosin contractions form medial and dorsolateral hinge points as neural folds bend and approach one another. D) Neural folds adhere to partner tissue and fuse, forming intact neural tube covered by NNE

Figure 3:. Disruption of NE proliferation

A) Illustration of proper balance of dorsal/ventral proliferation. Pax3 acts to increase proliferation dorsally, while Phactr4 acts to inhibit proliferation ventrally. B) Mice lacking Phactr4 display abnormal ventral NE proliferation (unexpected cells shown in red). Buildup of cells ventrally changes the geometry, which does not allow proper neural fold bending and inhibits closure.

Figure 4:. Disruption of mesoderm proliferation

A) Illustration of proper mesoderm proliferation and migration, highlighting Twist1 and Cart1 as necessary for bulging of mesoderm. B) Loss of Twist1 or Cart1 causes NE proliferation to outpace mesoderm growth, preventing the neural folds to adopt a concave orientation.

Figure 5:. Disruption of cell migration & intercalation

A) Illustration of NE cell sheet with selected cells marked in purple. B) Convergent extensions movements drive the narrowing and lengthening of the cell sheet due to cell migration and intercalation. C) Disruptions to cell migration & intercalation result in a wide neural plate which prevents contact of neural folds.

Figure 6:. Disruption of actomyosin contraction

A) Illustration of components necessary for proper localization, contraction, and turnover of actomyosin. B) Disruption of actomyosin contraction inhibits formation of hinge points and neural fold bending.