Science Inventory

A developmental ontology-based computational model for mammalian neural tube closure


Heusinkveld, H., Y. Staal, R. Spencer, T. Knudsen, G. Daston, AND A. Piersma. A developmental ontology-based computational model for mammalian neural tube closure. Society of Toxicology, Anaheim, CA, March 15 - 19, 2020.


Poster presentation at SOT 2020


Computational models of biological processes are expected to revolutionize chemical safety assessment in the not too far future. Such models provide the template for establishing quantitative adverse outcome pathway (AOP) networks that define critical key events that need monitoring in in vitro cell models, and provide algorithms for data integration towards defining safety profiles of chemicals at the level of the intact human. This project aims at modelling mammalian neural tube closure in silico, as a tool for defining the related AOP network and its critical key events that need monitoring in selected in vitro assays. The starting point was the retinoic acid pathway, given that this morphogen plays a crucial role in cell fate, pattern formation and morphogenesis in the early mammalian embryo. We have extensively mined the developmental biology and toxicology literature to generate the gene and cell compartment interaction map including ±40 genes and 6 cell compartments and their interactions. A cascade of gene expression changes programmed in the embryo in space and time causes location-specific cell proliferation and differentiation patterns, ultimately resulting in the development of a closed neural tube from the initial neural plate. For example, notochord-derived sonic hedgehog drives medial hinge point formation in the neural plate, followed by dorsolateral hinge point formation by noggin. Neural tube closure and neural crest cell delamination are mediated a.o. by E- and N-cadherin expression driven by Snai1 and Slug. Epidermis formation over the closed neural tube is induced by Smad1. Longitudinal neural proliferation versus differentiation is driven by gradients of retinoic acid versus Wnt rostrally and Fgf8 caudally. We have translated this map, produced in CellDesigner software, into a three-dimensional in silico neural tube closure model, produced in CC3D software, which is driven by the gene expression map. This model visualizes neural tube closure, starting from a flat surface of ectoderm in which the notochord triggers formation of the median hinge points causing the first invagination of the neural plate, after which closure of the tube occurs following formation of the dorsolateral hinge points. Subsequently, the neuroectoderm and the non-neuroectoderm fuse and the neural crest cells detach and migrate away from the fusion area. This model will allow to study in silico the consequences for neural tube closure of model compound-induced gene expression changes detected in relevant in vitro assays. This abstract does not necessarily reflect EPA policy.

Record Details:

Product Published Date: 03/19/2020
Record Last Revised: 08/20/2020
OMB Category: Other
Record ID: 349546