Neural crest as a way of knowing: new perspectives on lineage and morphogenesis.

Abstract

In a geographically remote, naturally beautiful, pristine site on Mt. Hood, Oregon, 100 scientists met for two days in June to celebrate the life and work of James A. Weston and to consider the current status of the field he so fruitfully cultivated, the neural crest. Where have we been? Where are we now? Where should we be going? What is neural crest and why is it important to understand? The neural crest is a migratory embryonic cell population that forms at the border of ectoderm and neural plate and differentiates into many cell types. From the perspective of the National Institutes of Health (NIH), understanding the biology of the neural crest is of critical importance. In the United States, 4% of all live births are estimated to have major birth defects, and birth defects are the leading cause of infant mortality, accounting for one in five infant deaths. Many craniofacial defects, some heart abnormalities, enteric nervous system defects, and others can be traced to abnormalities in neural crest biology. Moreover, neural crest is a microcosm of cell specification, patterning, migration, and differentiation and, thus, is a model for development as a whole. This review discusses highlights from this important cutting-edge meeting, which addressed key issues in lineage specification, delamination, and migration of the neural crest, with a major focus on the recurring and hotly debated theme of plasticity versus prepatterning. The meeting hosted an unusually wide spectrum of animal models, from larvacean urochordates to fly, fish, frog, chick, quail, duck, mouse, and marsupial, each providing its own insights. Researchers accustomed to attending the “fly meeting” or the “zebrafish meeting” extolled enthusiastically the utility of comparing work from multiple models. Such comparisons let us discover and extrapolate principles to other systems, and to humans. Lineage specification is an area of growing excitement for neural crest researchers, due not least to the vast number of neural crest derivatives available for investigation, or to the expanding numbers of molecular pathways implicated in this aspect of embryonic patterning, or even to the increasing number of experimental tools available across several model organisms. Most exciting, current results support a new conceptual archetype in whichmany neural crest subtypes may be segregated early and even spatially organized. The earliest segregation is thought to be that of the neural crest itself from adjacent ectodermal rudiments. Initial specification is due to an interaction at the border of neural plate and epidermis that produces a gradient of bone morphogenetic protein (BMP) activity. Roberto Mayor (University of Chile) discriminated among multiple steps in this induction and highlighted the downstream target of BMPasMsx, which was shown to be upstream of Snail and Slug. The concentrations of BMP required to induce msx1 expression were determined in both Xenopus and zebrafish, and supported a model in which Hairy2A represses Bmp4 transcription to ensure the optimal level of BMP. Hairy2A is positively controlled by Xiro1, which is upstream of Delta1 at the borders of the neural crest, with Snail acting as a repressor. Studies described by Judith Eisen (University of Oregon), provided evidence for temporal and spatial segregation among different neural crest precursors and for lateral inhibition and hierarchical choices that dictate cell type. In zebrafish, crest cells located dorsomedial to the trunk neural tube are later migrating and nonneurogenic, whereas those located more dorsolaterally are early migrating and neurogenic; these dorsolaterally located cells are the only ones that normally generate the dorsal root ganglion neurons. Without Delta/Notch signaling, there is a tradeoff among derivatives from the lateral edges of the neural plate that results in supernu-