Discussion and Conclusions

The finite element simulation presented here is the first published full-embryo model of neurulation. In time, it will be refined, as were its 2D predecessors, so that differences between the model and real embryos can be eliminated. The process of resolving these differences is an important scientific task because through it, deficits in understanding can be identified and relevant new experiments conceived.

The model demonstrates that realistic tissue motions are possible when a suitable cell-based constitutive equation is used. A key feature of the current constitutive model is that cells are able to flow past each other in-plane, a characteristic known to be important in real embryos. In previous (unpublished) attempts to model neurulation in 3 dimensions, cells were not free to rearrange in plane. This deficiency caused the tissues to be excessively stiff, especially with respect to in-plane shear, and it impeded the complex 3D deformations that must occur near the ends of the neural plate region. The present constitutive equation also made it possible for single finite elements to model multiple cells, making whole-embryo models computationally practical.

Recent experiments have shown that, during development, the fabric of the embryonic epithelia varies substantially with tissue type, location, and development stage. The constitutive model used here is able to successfully predict fabric evolution during in vitro tests, but additional statistical analysis software must be written before the accuracy of those predictions can be assessed in the context of neurulation. Such comparisons, however, are important to full model validation.

The constitutive model is structured so that, as the molecular pathways involved in tissue regulation are identified, their effects can be incorporated into the model. The model can hence serve as a bridge between gene expression and the morphogenetic movements of critical developmental events. This important integration of biology and mechanics is possible because the finite element method provides an open computational framework.

Simulations conducted to date show that tissue motions are highly sensitive to the geometry of the initial configuration and to tissue mechanical properties. This finding suggests that spina bifida and other neural tube defects might arise through a variety of subtle mechanical means. It also suggests that modest interventions might be sufficient to prevent neural tube defects. Identifying appropriate intervention methods is a critical goal for additional research, and the finite element model presented here holds promise as means to carry out preliminary evaluations of proposed interventions.

Acknowledgements

This research was funded by the Canadian Institutes of Health Research (CIHR). Animals were cared for in accordance with Canadian Council on Animal Care (CCAC) guidelines.

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