*Corresponding Author: Heather C. Etchevers—INSERM U393, Hôpital Necker – Enfants Malades, 149 rue de Sèvres, 75743 Paris Cedex 15, France. Email: etchevers@necker.fr Neural Crest Induction and Differentiation, edited by Jean-Pierre Saint-Jeannet. ©2006 Eurekah.com. Molecular Bases of Human Neurocristopathies Heather C. Etchevers,* Jeanne Amiel and Stanislas Lyonnet Introduction N eural crest cells (NCC) form in the human embryo during the third to fifth weeks of pregnancy, within the neural folds that delineate the neural plate from the ectoderm. During the fusion of the neural folds, which ultimately yields a tube that will become the central nervous system (CNS), NCC detach and become mesenchymal. They migrate throughout the body, integrating nearly every organ. NCC derivatives include the neurons and support cells of the entire peripheral nervous system (sensory and autonomic), adrenergic and other endocrine cells, and all pigment cells except those arising from the retina (reviewed by Le Douarin and Kalcheim 1 ). In the head, in addition to the cell types mentioned above, NCC differentiate into connective and struc- tural tissues such as dermis, 2,3 bones and cartilage of most of the skull 3,4 and muscle tendons. 5,6 They also infiltrate and are essential for the function of glandular and vascular elements such as the thymus, the thyroid and parathyroid glands, the conotruncal region of the heart and the entire branchial vascular sector, 7-9 giving rise to connective, adipose and smooth muscle cells. The astonishing diversity of NCC derivatives has led to this population being nicknamed the “fourth embryonic germ layer.” The fact that NCC were known to exist only in the embryo precluded their being perceived as a true stem cell type. Recently, however, it was demonstrated that the enteric nervous system of the adult rat contains neural crest stem cells that self-renew and remain oligopotent. 10 Avian melanocytes are able to transdifferentiate into glial cells, neurons or smooth muscle-like cells in vitro, also implying the long-term existence of multipotent progenitors. 11 It is thought that NCC derivatives are generated through progressive restriction of developmental potential. 12,13 The ultimate choice in phenotype made at a given site of differentiation is the result of a combination of extrinsic factors in the embryonic microenvironment and cell-intrinsic properties that modify its responsiveness to these external influences. The former have been documented through observation of the disruption of neurotrophic growth factors and receptor genes that result in deficiencies of selected subsets of NCC derivatives. 14,15 Both their migration pathways and fate are imposed on NCC by surrounding tissues as they leave the neural primordium; these are not dependent on intrinsic properties regionally distributed along the neuraxis, as had initially been presumed. For instance, truncal NCC transplanted at the vagal level colonize the gut and differentiate into enteric ganglia in which neurons synthesize acetyl- choline rather than catecholamines, as they would have done normally at the truncal level. 3 A notable exception, the cephalic NCC contributing to the branchial arch-derived facial skeleton has some intrinsic positional information and commitment, 16,17 apparently imparted by the rostral endoderm before and during their emigration from the neural folds. 18,19