Molecular analysis of neural crest formation.

Neural crest cells arise within the ectoderm during neurulation and give rise to most of the peripheral nervous system. Following neural tube closure, they come to lie within the dorsal neural tube from which they emerge and subsequently migrate extensively to numerous and characteristic sites. There, they differentiate into neurons and glia of the peripheral nervous system, cartilage and bone of the face, melanocytes and various other cell types. Fate mapping experiments have demonstrated that the neural crest arises at the juncture between presumptive epidermis and neural plate. However, injection of lineage tracer into individual cells reveals that single neural fold cells are not committed to a neural crest fate; rather these cells can form all ectodermal derivatives (epidermis, neural tube, neural crest). Inductive interactions between the neural and non-neural ectoderm can generate neural crest cells, suggesting that signals travel through the epidermis to generate neural crest cells prior to neural tube closure. Induction of the neural crest appears to be a multiphasic process and involves a combination of an early Wnt signal together with later functions of BMP signaling pathways. We have used a variety of molecular screens to isolate molecular constituents involved in neural crest formation. We have identified a secreted factor, Noelin-1, which is expressed in the prospective avian neural plate and may play a role making the neural tube competent to form neural crest. Noelin-1 mRNA is expressed in a graded pattern in the closing neural tube, with highest expression in the neural folds and no detectable expression at the ventral midline. Its expression precedes that of Slug, a zinc finger transcription factor that represents the earliest known neural crest marker gene. Over-expression of Noelin-1 using recombinant retroviruses causes an excess of neural crest emigration and prolongs the time that the neural tube is competent to generate and regenerate neural crest cells. These results support an important role for Noelin-1 in rendering the neural tube competent to respond to inductive cues to generate neural crest.