Cho, Y-J; (2015) Biomechanical mechanisms of neural tube closure. Doctoral thesis , UCL (University College London).

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Abstract

Neural tube defects (NTDs) are amongst the commonest birth defects, affecting 1 in 1000 pregnancies. During neurulation, failure of neural tube closure in the low spinal region (at the posterior neuropore, PNP) results in spina bifida. Mechanical force relationships in the normally closing neural tube and in the NTD-developing neural tube were investigated through incision of the most recently closed neural tube roof, in order to eliminate tension in the closed region. After incision in wild-type embryos, immediate springing apart (re-opening) of the elevating neural folds was observed, associated with partial relaxation of the bending degree of the Dorsolateral Hinge Points (DLHP) and the Median Hinge Point (MHP) in transverse sections. When incision was performed on Zic2 mutant embryos developing spina bifida, a larger re-opening of neural folds was observed than in wild-type controls. These findings coincided with measurements of the elastic modulus of the mutant NPs using Atomic Force Microscopy, which revealed that the dorsal NP of the mutant embryos is stiffer than wild-type. Finite Element Method (FEM) modelling also showed that a larger closing force is required for a stiffer NP. Moreover, in unincised embryos, nuclei were found to be more elongated in the wild-type NP, where DLHPs are present, than in the mutant NP, where DLHPs are absent, suggesting possible roles of cell packing in DLHP formation. In conclusion, apposition of the NFs is an elastic process exogenously driven by the force field that originates from the most recently closed point. DLHP formation, however, is a partially plastic process, closely related to cell packing within the dorsal NP as an endogenous event. In Zic2 mutant embryos, a stiffer NP and the absence of cell-packing in the dorsal NP region are perhaps the main mechanical causes of spinal neurulation failure.

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