Abstract
Epithelial fusion is a crucial process in embryonic development, and its failure underlies several clinically important birth defects. For example, failure of neural fold fusion during neurulation leads to open neural tube defects including spina bifida. Using mouse embryos, we show that cell protrusions emanating from the apposed neural fold tips, at the interface between the neuroepithelium and the surface ectoderm, are required for completion of neural tube closure. By genetically ablating the cytoskeletal regulators Rac1 or Cdc42 in the dorsal neuroepithelium, or in the surface ectoderm, we show that these protrusions originate from surface ectodermal cells and that Rac1 is necessary for the formation of membrane ruffles which typify late closure stages, whereas Cdc42 is required for the predominance of filopodia in early neurulation. This study provides evidence for the essential role and molecular regulation of membrane protrusions prior to fusion of a key organ primordium in mammalian development.
Highlights
The fusion of apposed epithelial sheets is an essential process in the completion of many morphogenetic events including closure of the neural tube, optic fissure, palatal shelves, and cardiac septa
We show that Rac1 regulates the formation of ruffles, without which neurulation fails leading to open spina bifida, whereas Cdc42 is implicated in the formation of filopodia during earlier stages of neurulation
The sectional views obtained with transmission electronic microscopy (TEM) do not allow for a three-dimensional analysis of protrusive morphology
Summary
The fusion of apposed epithelial sheets is an essential process in the completion of many morphogenetic events including closure of the neural tube, optic fissure, palatal shelves, and cardiac septa. Failure of these fusion events leads to clinically important congenital malformations including neural tube defects (NTDs: anencephaly and open spina bifida), coloboma, cleft palate, and cardiac septal defects, respectively (Pai et al, 2012; Ray and Niswander, 2012). Understanding the mechanisms by which the vertebrate neural plate folds up and fuses to form a closed neural tube is of paramount importance for gaining insight into the embryonic pathogenesis of NTDs, and for developing improved methods for their prevention. About the final steps of neurulation, involving fusion and remodelling of the neural folds at the dorsal midline
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