The neural crest and neural crest defects

The neural crest and neural crest defects
Maya Sieber-Blum andZhijian Zhang (USA)

The neural crest is a fascinating embryonic tissue for more than one reason. In the adult organism it gives rise to an array of distinct cell types and tissues. It is responsible for many birth defects, familial diseases and malignancies, and it is amenable to the elucidation of mechanisms that regulate stem cell differentiation. Subsequent to an epithelial-to-mesenchymal transforma­tion, neural crest cells emigrate from the dorsal aspect of the neural tube into the embryo, stop in different places, and eventually give rise to the autonomic and enteric nervous systems, most primary sensory neurons, endocrine cells, and melanocytes of the skin and internal organs. Furthermore, neural crest cells are involved in the septation of the cardiac outflow tract and they form the cranial mesenchyme, which gives rise to bone, cartilage, and connective tissue of the face and ventral neck. Environmental insults can lead to neural crest defects, including cleft lip/cleft palate and fetal alcohol syndrome. Familial diseases that affect neural crest derivatives include Hischsprung’s disease and albinism, whereas well-known neural crest-related malignancies include melanoma, neuroblastoma, neurofibromatosis and pheochromocytoma. Migratory neural crest cells form a heteroge­neous population of cells that includes stem cells, cells with restricted developmental potentials, and cells that are committed to a particular lineage. Growth factors play important roles in the survival, proliferation and differentiation of neural crest cells. In particular, neurotrophin-3 (NTS), the ligand of the tyrosine kinase receptor, TrkC, promotes the survival of proliferating neural crest stem cells. TrkC-deficient mice develop cardiac outflow tract defects that resemble human birth defects, including persistent truncus arteriosus and transposition of the great vessels. In these animals, cardiac neural crest stem cells become fate-restricted precociously. Action of stem cell factor (SCF), the ligand of the tyrosine kinase receptor c-kit, affects multiple systems. Heterozygous c-kit deficient mice, termed ‘Dominant spotting’ (W), have anemia, are sterile and show changes in coat color (white spotting) due to defects in the hemopoietic system, germ cell line and melanogenesis, respectively. Inactivation of the human c-kit gene causes piebaldism, which is characterized by a white forelock, patchy hypopigmentation of the skin and rare sensoryneural deafness. In the quail neural crest, SCF supports the survival of neural crest stem cells, promotes their dif­ferentiation into small diameter sensory neurons, and, together with a neurotrophin, supports survival of me lanocyte precursors. In c-kit deficient newborn mice, up to one third of substance P-immunoreactive nociceptive sensory neurons are missing, thus confirming across species that SCF signaling is essential for the development of small diameter sensory neurons. In addition, the number of calcitonin gene-related-peptide (CGRP)-immunoreactive putative visceral afferent neurons in the dorsal root ganglion is diminished in these mice. The norepinephrine transporter (NET) is expressed in many embryonic tissues, including premigratory and migratory neural crest cells. Norepinephrine (NE) uptake by neural crest cells promotes their differentiation into noradrenergic neuroblasts in vitro. In contrast, NE uptake inhibitors, such as tricyclic antidepressants and the drug of abuse, cocaine, inhibit noradrenergic differentiation in vitro and in vivo, suggesting that these drugs can be teratogenic. Since NET is expressed in many embryonic tissues, NE transport may have functions also in non-neural cells during embryonic development. In summary, growth factors, alone and synergistically as well as NEplay multiple roles in neural crest development.
Biomed Rev 2002; 13: 29-37.
Received 13 May 2002 and accepted 15 July 2002.

Correspondence and reprint requests to Dr Maya Sieber-Blum, Department of Cell Biology, Neurobiology and Anatomy. Medical College of Wisconsin, 8701 Watertown Plank Road, Milwaukee, Wisconsin 53226, USA. Tel: 414-456-8465, Fax: 414-456-6517

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