Dishevelled, convergent extension, and neural tube closure
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Vertebrate neurulation involves a precisely orchestrated set of morphogenetic movements within the neural plate, including elongation and shaping of the neural plate; elevation and apposition of the neural folds; and fusion of the folds at the dorsal midline. Human neural tube defects (NTDs) stem from a failure of one or more of these morphogenetic processes. While recent genetic experiments in mice have identified many individual genes that are critical to neural tube closure, the molecular basis and embryological underpinnings of most human neural tube defects remain poorly understood. Because amphibian embryos develop externally, they are ideally suited for studying morphogenetic movements such as neural tube closure.

We have shown that during amphibian development, dishevelled (Xdsh) signaling controls the convergent extension of neural tissues, and that loss of Xdsh function results in a failure of neural tube closure (seeDevelopment 129, 5815-5825 and Development, 128, 2581-2592 ). Time-lapse microscopy (see movies here) and targeted injections revealed that Xdsh signaling is not required for neural fold elevation, medial movement, or fusion. Disruption of Xdsh signaling therefore provides a specific tool for uncoupling convergent extension from other processes of neurulation. Using disruption of Xdsh signaling, we demonstrate that convergent extension is critical to tube closure.

Our data indicate that the inherent movement of the neural folds can accomplish only a finite amount of medial progress and that convergent extension of the midline is necessary to reduce the distance between the nascent neural folds, allowing them to meet and fuse. Because human embryos with craniorachischisis and mice in which PCP signaling has been disrupted also display shortened axes and broad, open neural tubes, our data suggest that this type of neural tube defect may result generally from a failure of convergent extension.

We are continuing these studies and are also now examining molecules that control other critical events during neurulation. For these studies we are taking advantage of the axolotl, Ambystoma mexicanum. Axolotl neurulation is quite robust and closely resembles mammalian neurulation (time-lapse movies here). Becasue the axolotl is amenable to the same manipulations as Xenopus, we hope that this embryo will help us to discern the details of neural tube closure.
Shroom and cell shape change during neural tube clsoure

We have recently begun to explore other morphogenetic mechanisms that contribute to neural tube closure. The conversion of columnar cells to wedge shaped cells, called "apical constriction," is commonly observed in bending epithelial sheets. We have recently shown that the actin binding protein, Shroom, controls this process (Current Biology 13, 2125-2137. In fact, ectopic expression of Shroom in naive epithelial cells is sufficient to induce ectopic apical constrictions. This result suggests that bending of epithelial sheets can be patterned by controlled expression of a very smal number of genes. We are now exploring the mechanisms of Shroom function
Ambystoma mexicanum