Neurulation occurs during the early embryogenesis of chordates, and it results in the formation of the neural tube, a dorsal hollow nerve cord that constitutes the rudiment of the entire adult central nervous system. The goal of studies on neurulation is to understand its tissue, cellular and molecular basis, as well as how neurulation is perturbed during the formation of neural tube defects. The tissue basis of neurulation consists of a series of coordinated morphogenetic movements within the primitive streak (e.g., regression of Hensen's node) and nascent primary germ layers formed during gastrulation. Signaling occurs between Hensen's node and the nascent ectoderm, initiating neurulation by inducing the neural plate (i.e., actually, by suppressing development of the epidermal ectoderm). Tissue movements subsequently result in shaping and bending of the neural plate and closure of the neural groove. The cellular basis of the tissue movements of neurulation consists of changes in the behavior of the constituent cells; namely, changes in cell number, position, shape, size and adhesion. Neurulation, like any morphogenetic event, occurs within the milieu of generic biophysical determinants of form present in all living tissues. Such forces govern and to some degree control morphogenesis in a tissue-autonomous manner. The molecular basis of neurulation remains largely unknown, but we suggest that neurulation genes have evolved to work in concert with such determinants, so that appropriate changes occur in the behaviors of the correct populations of cells at the correct time, maximizing the efficiency of neurulation and leading to heritable speciesand axial-differences in this process. In this article, we review the tissue and cellular basis of neurulation and provide strategies to determine its molecular basis. We expect that such strategies will lead to the identification in the near future of critical neurulation genes, genes that when mutated perturb neurulation in a highly specific and predictable fashion and cause neurulation defects, thereby contributing to the formation of neural tube defects.

Tissue manipulation experiments in amphibians more than 50 years ago showed that induction of the inner ear requires two signals: a mesodermal signal followed by a neural signal. However, the molecules mediating this process have remained elusive. We present evidence for mesodermal initiation of otic development in higher vertebrates and show that the mesoderm can direct terminal differentiation of the inner ear in rostral ectoderm. Furthermore, we demonstrate the synergistic interactions of the extracellular polypeptide ligands FGF-19 and Wnt-8c as mediators of mesodermal and neural signals, respectively, initiating inner ear development.

Development of the node and formation of the notochordal plate in gestational day 7-9 mice (Theiler stages 10-14) has been documented principally with scanning electron microscopy (SEM) and cell fate analyses utilizing DiI andlor CFSE as a cell label. With SEM, cells composing these two populations are initially identifiable at stage 10 at the ventral midline of the rostral half of the embryo. They can be recognized by their relatively small ventral surface area, as compared to that of the peripherally adjacent prospective gut endodermal cells, and by the presence on the ventral side of each cell of a prominent single, central cilium, which is lacking on endodermal cells. At stage 10, the node is located at the apex of the cup-shaped embryo. It represents the rostral end of the primitive streak (although its structure differs from that of the rest of the streak), and it consists of a localized two-layered area (i.e., epiblast and the most caudal aspect of the notochordal plate). By stage 11, the notochordal plate constitutes a relatively broad, circular area (at the level of the node) that tapers rostrally into a narrower midline strip (beneath the future floor plate of the neural tube). The tip of the notochordal plate terminates rostrally at the much broader prechordal plate, which underlies the future forebrain level of the neuraxis. The prechordal plate cells, like the ventral node and notochordal plate cells, each have a relatively small ventral surface area and displays a single central cilium on their ventral surface. The most caudal aspect of the notochordal plate remains morphologically distinct on the dorsal, midline surface of the open gut through stage 13; the more rostral levels progressively fold off from the roof of the gut to form the definitive notochord. Videomicroscopy reveals that the cilia extending from the ventral surfaces of the cells of node and of the prechordal and notochordal plates are motile. The potential significance of this motile behavior remains unknown. Labeling studies, which marked cells in both the dorsal and ventral layers of the node, reveal that the stage-10 node contributes cells to the notochordal plate and overlying midline ectodermal cells of the neural plate, the future floor plate of the neural tube. The results of our labeling studies, in which cells in both layers of the node were marked, when compared with the 0 1994 WILEY-LISS, INC. results of a recent study in which only the ventral layer of the node was marked (Beddington [19941 Development 1206134320) provide strong evidence that the ventral layer of the node forms notochord, whereas the dorsal layer forms floor plate of the neural tube. A similar origin for these two populations of cells has been suggested for the chick embryo (Selleck and Stern [19911 Development 112615-626). The morphology of the murine notochordal plate and labeling studies support the concept of origin and rostrocaudal elongation of this structure in large part by accretion of cells from the node. In addition, cell division a...

In both chick and mouse, the otic placode, the rudiment of the inner ear, is induced by at least two signals, one from the cephalic paraxial mesoderm and the other from the neural ectoderm. In chick, the mesodermal signal, FGF19, induces neural ectoderm to express additional signals, including WNT8c and FGF3, resulting in induction of the otic placode. In mouse, mesodermal Fgf10 acting redundantly with neural Fgf3 is required for induction of the placode. To determine how the mesodermal inducers of the otic placode are localized, we took advantage of the unique strengths of the two model organisms. We show that endoderm is necessary for otic induction in the chick and that Fgf8, expressed in the chick endoderm subjacent to Fgf19, is both sufficient and necessary for the expression of Fgf19 in the mesoderm. In the mouse, Fgf8 is also expressed in endoderm as well as in other germ layers in the periotic placode region. We show that otic induction fails in embryos null for Fgf3 and hypomorphic for Fgf8 and expression of mesodermal Fgf10 is reduced. Thus, Fgf8 plays a critical upstream role in an FGF signaling cascade required for otic induction in chick and mouse.

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