Epithelial fusion during neural tube morphogenesis

Abstract

Adhesion and fusion of epithelial sheets marks the completion of many morphogenetic events during embryogenesis. Neural tube closure involves an epithelial fusion sequence in which the apposing neural folds adhere initially via cellular protrusions, proceed to a more stable union, and subsequently undergo remodeling of the epithelial structures to yield a separate neural tube roof plate and overlying nonneural ectoderm. Cellular protrusions comprise lamellipodia and filopodia, and studies in several different systems emphasize the critical role of RhoGTPases in their regulation. How epithelia establish initial adhesion is poorly understood but, in neurulation, may involve interactions between EphA receptors and their ephrinA ligands. Epithelial remodeling is spatially and temporally correlated with apoptosis in the dorsal neural tube midline, but experimental inhibition of this cell death does not prevent fusion and remodeling. A variety of molecular signaling systems have been implicated in the late events of morphogenesis, but genetic redundancy, for example among the integrins and laminins, makes identification of the critical players challenging. An improved understanding of epithelial fusion can provide insights into normal developmental processes and may also indicate the mode of origin of clinically important birth defects.

Figure 1

Diagrammatic representation of the late events in mammalian spinal neural tube closure. (A) Regulated bending of the neural plate at both median (MHP) and dorsolateral (DLHP) hinge points brings the neural fold tips into apposition in the dorsal midline. (B) Epithelial protrusions are visible emanating from the fold tips, and making the first contact across the gap between neural folds. (C) Epithelial adhesion occurs together with onset of remodelling, in which the continuity of the surface ectoderm-neuroepithelium layer is broken on each side. (D) Epithelial continuity is re-established with formation of a continuous neural tube roof plate and overlying surface ectoderm.

Figure 2

Scanning electron micrographs of the dorsal aspect of a mouse embryo at embryonic day (E) 9.5. (A) Back view of the whole embryo. The neural tube is completely closed except for the posterior neuropore in the spinal region. Boxed area is the closure point of the neuropore, where cellular protrusions are most abundantly seen. (B) Enlargement of the boxed area in A. the polygonal outlines of the surface ectoderm cells are clearly visible, as are cellular protrusions emanating from the edges of the neural folds as they approach each other in the midline. (C) Higher magnification of the boxed area in B. The cellular protrusions can be seen as complex, three dimensional cellular lamellipodia (also called membrane ‘ruffles’). Note that the lamellipodia appear to emerge from the junction between the surface ectoderm and the neural plate, which forms the inner lining of the posterior neuropore.