An ontology for developmental processes and toxicities of neural tube closure

• Published in: Reproductive toxicology (Elmsford, N.Y.) Vol. 99; pp. 160 - 167
• Main Authors: Heusinkveld, Harm J., Staal, Yvonne C.M., Baker, Nancy C., Daston, George, Knudsen, Thomas B., Piersma, Aldert
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.01.2021
• Subjects: Animals; Computer Simulation; Developmental neurotoxicology; Ectoderm; Embryonic Development; Humans; Mesoderm; Mice; Models, Biological; Neural Crest; Neural Plate; Neural Tube - growth & development; Neural tube defect; Neural Tube Defects; Notochord; Retinoic acid; Systems Biology; Tretinoin - metabolism; Developmental neurotoxicology; Systems biology; Retinoic acid; Neural tube defect
• ISSN: 0890-6238; 1873-1708
• DOI: 10.1016/j.reprotox.2020.09.002

•Molecular processes of neural tube closure can be visualized in a computational model.•Neural tube differentiation and closure is guided by gradients along the body axes•Key steps in physiology and biomechanics of neural tube closure have been identified.•Identification of key steps allows for development of a 3R-based toxicological model. In recent years, the development and implementation of animal-free approaches to chemical and pharmaceutical hazard and risk assessment has taken off. Alternative approaches are being developed starting from the perspective of human biology and physiology. Neural tube closure is a vital step that occurs early in human development. Correct closure of the neural tube depends on a complex interplay between proteins along a number of protein concentration gradients. The sensitivity of neural tube closure to chemical disturbance of signalling pathways such as the retinoid pathway, is well known. To map the pathways underlying neural tube closure, literature data on the molecular regulation of neural tube closure were collected. As the process of neural tube closure is highly conserved in vertebrates, the extensive literature available for the mouse was used whilst considering its relevance for humans. Thus, important cell compartments, regulatory pathways, and protein interactions essential for neural tube closure under physiological circumstances were identified and mapped. An understanding of aberrant processes leading to neural tube defects (NTDs) requires detailed maps of neural tube embryology, including the complex genetic signals and responses underlying critical cellular dynamical and biomechanical processes. The retinoid signaling pathway serves as a case study for this ontology because of well-defined crosstalk with the genetic control of neural tube patterning and morphogenesis. It is a known target for mechanistically-diverse chemical structures that disrupt neural tube closure The data presented in this manuscript will set the stage for constructing mathematical models and computer simulation of neural tube closure for human-relevant AOPs and predictive toxicology.