Abstract
SummaryBending of the neural plate at paired dorsolateral hinge points (DLHPs) is required for neural tube closure in the spinal region of the mouse embryo. As a step towards understanding the morphogenetic mechanism of DLHP development, we examined variations in neural plate cellular architecture and proliferation during closure. Neuroepithelial cells within the median hinge point (MHP) contain nuclei that are mainly basally located and undergo relatively slow proliferation, with a 7 h cell cycle length. In contrast, cells in the dorsolateral neuroepithelium, including the DLHP, exhibit nuclei distributed throughout the apico-basal axis and undergo rapid proliferation, with a 4 h cell cycle length. As the neural folds elevate, cell numbers increase to a greater extent in the dorsolateral neural plate that contacts the surface ectoderm, compared with the more ventromedial neural plate where cells contact paraxial mesoderm and notochord. This marked increase in dorsolateral cell number cannot be accounted for solely on the basis of enhanced cell proliferation in this region. We hypothesised that neuroepithelial cells may translocate in a ventral-to-dorsal direction as DLHP formation occurs, and this was confirmed by vital cell labelling in cultured embryos. The translocation of cells into the neural fold, together with its more rapid cell proliferation, leads to an increase in cell density dorsolaterally compared with the more ventromedial neural plate. These findings suggest a model in which DLHP formation may proceed through ‘buckling’ of the neuroepithelium at a dorso-ventral boundary marked by a change in cell-packing density.
Highlights
IntroductionThe Zic2-mutant mouse fails to develop dorsolateral hinge points (DLHPs) and subsequently exhibits extensive spina bifida (Elms et al, 2003; Ybot-Gonzalez et al, 2007), demonstrating the critical requirement for DLHP formation in the closure of the spinal neural tube
Mouse neural tube closure is initiated at E8.5, at the hindbraincervical boundary (Closure 1), with neurulation propagating rostrally into the hindbrain, and caudally along the trunk, from this level
Apico-basal nuclear localisation, neural plate width, neural plate and surface ectodermal cell numbers, and nominal cell widths and density were analysed at two levels of each posterior neuropore (PNP): caudally, where the folding of the neural plate begins (‘flat’ neural plate; Fig. 1 C,G,K), and rostrally, where the neural folds are nearing completion of closure (‘elevated’ neural plate; Fig. 1D,H,L)
Summary
The Zic2-mutant mouse fails to develop DLHPs and subsequently exhibits extensive spina bifida (Elms et al, 2003; Ybot-Gonzalez et al, 2007), demonstrating the critical requirement for DLHP formation in the closure of the spinal neural tube. MHP bending is stimulated by notochordal factors including sonic hedgehog (Shh), whereas DLHP formation is simultaneously inhibited by Shh (Ybot-Gonzalez et al, 2002). Shh is expressed strongly in the notochord and suppresses Noggin-mediated DLHP formation whereas, in the low spine, Shh production from the notochord is greatly diminished, Noggin is de-repressed, blocks BMP2 action, and DLHP formation occurs (Ybot-Gonzalez et al, 2007)
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