The continuing challenge of understanding, preventing, and treating neural tube defects

Abstract

Human birth defects are a major public health burden: The Center for Disease Control estimates that 1 of every 33 United States newborns presents with a birth defect, and worldwide the estimate approaches 6% of all births. Among the most common and debilitating of human birth defects are those affecting the formation of the neural tube, the precursor to the central nervous system. Neural tube defects (NTDs) arise from a complex combination of genetic and environmental interactions. Although substantial advances have been made in the prevention and treatment of these malformations, NTDs remain a substantial public health problem, and we are only now beginning to understand their etiology. Here, we review the process of neural tube development and how defects in this process lead to NTDs, both in humans and in the animal models that serve to inform our understanding of these processes. The insights we are gaining will help generate new intervention strategies to tackle the clinical challenges and to alleviate the personal and societal burdens that accompany these defects.

Figure 1

A. Successive images showing the time course of neural tube closure in a stylized vertebrate embryo (rostral = up). Initially, the CNS is a flat sheet; paired neural folds elevate along the rostrocaudal axis and move medially, eventually fusing to enclose the neural tube. B. Cross-sections illustrate closed (red) and open (green) regions of the neural tube. C. Region-specific neural tube defects.

Figure 2

A. Still frames from a time lapse movie showing neural tube closure in an amphibian embryo (rostral = up). B. Disruption of PCP signaling results in disrupted neural tube closure (red bracket). C. Still frame from a movie of mouse neural tube closure; arrows indicate initial meeting of neural folds (47). c′. Neural tube closure has progressed in a later time point. D. Genetically-inducible fluorescent reporters allow visualization of specific tissues (green), in this case the ectoderm that borders the neural tissue.

Figure 3

A. Convergent extension cell behavior elongates a tissue (the cell sheet is viewed en face). B. Apical constriction cell behavior transforms a columnar cell into a wedge shape. b′ Localized apical constriction bends cell sheets (viewed here in cross section).