Melanocytes, the pigmented cells of the skin, and the glial Schwann cells lining 
peripheral nerves are developmentally derived from an early and transient 
ectodermal structure of the vertebrate embryo, the neural crest, which is also 
at the origin of multiple neural and non-neural cell types. Besides melanocytes 
and neural cells of the peripheral nervous system, the neural crest cells give 
rise to mesenchymal cell types in the head, which form most of the craniofacial 
skeleton, dermis, fat tissue and vascular musculo-connective components. How 
such a wide diversity of differentiation fates is established during 
embryogenesis and is later maintained in adult tissues are among key questions 
in developmental and stem cell biology. The analysis of the developmental 
potentials of single neural crest cells cultured in vitro led to characterizing 
multipotent stem/progenitor cells as well as more restricted precursors in the 
early neural crest of avian and mammalian embryos. Data support a hierarchical 
model of the diversification of neural crest lineages through progressive 
restrictions of multipotent stem cell potentials driven by local environmental 
factors. In particular, melanocytes and glial Schwann cells were shown to arise 
from a common bipotent progenitor, which depends upon the peptide endothelin-3 
for proliferation and self-renewal ability. In vivo, signaling by endothelin-3 
and its receptor is also required for the early development of melanocytes and 
proper pigmentation of the vertebrate body. It is generally assumed that, after 
lineage specification and terminal differentiation, specialized cell types, like 
the melanocytes and Schwann cells, do not change their identity. However, this 
classic notion that somatic cell differentiation is a stable and irreversible 
process has been challenged by emerging evidence that dedifferentiation can 
occur in different biological systems through nuclear transfer, cell fusion, 
epigenetic modifications and ectopic gene expression. This review considers the 
issue of whether neural crest-derived lineages are endowed with some phenotypic 
plasticity. Emphasis is put on the ability of pigment cells and Schwann cells to 
dedifferentiate and reprogram their fate in vitro. To address this question, we 
have studied the clonal progeny of differentiated Schwann cells and melanocytes 
after their isolation from the sciatic nerve and the back skin of quail embryos, 
respectively. When stimulated to proliferate in vitro in the presence of 
endothelin-3, both cell types were able to dedifferentiate and produce 
alternative neural crest-derived cell lineages. Individual Schwann cells 
isolated by FACS, using a glial-specific surface marker, gave rise in culture to 
pigment cells and myofibroblasts/smooth muscle cells. Treatment of the cultures 
with endothelin-3 was required for Schwann cell conversion into melanocytes, 
which involved acquisition of multipotency. Moreover, Schwann cell plasticity 
could also be induced in vivo: following transplantation into the branchial arch 
of a young chick host embryo, dedifferentiating Schwann cells were able to 
integrate the forming head structures of the host and, specifically, to 
contribute smooth muscle cells to the wall of cranial blood vessels. We also 
analyzed the in vitro behavior of individual pigment cells obtained by 
microdissection and enzymatic treatment of quail epidermis at embryonic and 
hatching stages. In single cell cultures treated with endothelin-3, pigment 
cells strongly proliferated while rapidly dedifferentiating into unpigmented 
cells, leading to the formation of large colonies that comprised glial cells and 
myofibroblasts in addition to melanocytes. By serially subcloning these primary 
colonies, we could efficiently propagate a bipotent glial-melanocytic precursor 
that is generated in the progeny of the melanocytic founder. These data 
therefore suggest that pigment cells have the ability to revert back to the 
state of self-renewing neural crest-like progenitors. Altogether, these studies 
have shown that Schwann cells and pigment cells display an unstable status of 
differentiation, which can be disclosed if these differentiated cells are 
displaced out of their native tissue. When challenged with new environmental 
conditions in vitro, differentiated Schwann cells and pigment cells can 
reacquire stem cell properties of their neural crest ancestors. Notably, such 
reprogramming was achieved through the effect of a single exogenous factor and 
without the need of any induced genetic modification. Deciphering the cellular 
and molecular mechanisms that regulate the plasticity and maintenance of neural 
crest-derived differentiated cells is likely to be an important step towards the 
understanding of the neurocristopathies and cancers that target neural crest 
derivatives in humans.