Scientific Understanding of Consciousness
Consciousness as an Emergent Property of Thalamocortical Activity

Neural Crest Cell Development, Schwann Cells



Science 23 August 2013: Vol. 341 no. 6148 pp. 860-863

Tissue Interactions in Neural Crest Cell Development and Disease

Yoshiko Takahashi, Douglas Sipp, Hideki Enomoto

1Department of Zoology, Graduate School of Science, Kyoto University, Kitashirakawa, Sakyo-ku, Kyoto 606-8502, Japan.

2Japan Science and Technology Agency (JST), Core Research for Evolutional Science and Technology (CREST), Japan.

3Center for Developmental Biology, RIKEN, 2-2-3 Minatojima Minamimachi, Chuo-ku, Kobe 650-0047, Japan.

4Department of Physiology and Cell Biology, Graduate School of Medicine, Kobe University, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.


Neural Crest Emerges from Neural Tube

The neural crest is a transient, migratory population of multipotent cells that emerges from the dorsal aspect of the neural tube during early vertebrate development and gives rise to a remarkable variety of differentiated cell types, including sensory, autonomic, and enteric ganglia in the peripheral nervous system; the adrenal medulla; melanocytes; and a range of skeletal, connective, adipose, and endocrine cells.

Here, we describe how interactions between cells of the neural crest and lineages such as the vascular system, as well as those involving environmental signals and microbial pathogens, are critically important in determining the roles played by these cells.

Neural Crest Cells (NCCs) Long Range Migration through Embryo

The capacity for long-range migration through the embryo is a second defining feature of neural crest cells (NCCs). The journey these cells take across the dynamic landscape of the developing embryo exposes them to myriad signals from surrounding tissue microenvironments, which vary by developmental site and stage. The paths of migrating NCCs are directed by molecular guidance cues mediated by the binding of external ligands with receptors on the NCC surface. The differentiation, morphology, and patterning of neural crest derivatives and the tissues with which they interact are also influenced by local tissue interactions.

Genetically Determined Factors and Environmental Cues

Genetically determined cell-autonomous factors or exposure to environmental cues can result in inappropriate NCC differentiation, leading to ectopic tissue formation or an uncontrolled cell cycle. Defects in NCC function are associated with a number of serious diseases, many of which primarily affect pediatric patients. Thus, the great versatility and mobility of NCCs and their derivatives is a double-edged sword, capable of contributing to both normal embryogenesis and severe developmental pathologies.

Differentiation and Migration of NCCs

Advanced genetics and imaging technologies have begun to lift the veil on the in vivo differentiation and migration of NCCs, revealing a number of unexpected behaviors of these cells and their derivatives in the development of the adrenal medulla, sympathetic and enteric ganglia, and glial Schwann cells throughout the peripheral nervous system, as well as in vascular remodeling and hematopoiesis. In fulfilling their many roles, the cells of the neural crest work in close cooperation with other cells and tissues, and such interactions are now beginning to attract interest as potential targets in numerous diseases.

First Blood Vessel to Form during Embryogenesis, a Morphogenetic Signaling Center

More recently, researchers examined how the migration and differentiation of cells in these lineages are regulated in vivo, showing how the dorsal aorta, which is the first blood vessel to form during embryogenesis, functions as a morphogenetic signaling center that coordinates NCC migration and lineage segregation. In response to aortic bone morphogenetic protein (BMP) signals, precursor cells differentiate into separate sympathetic and adrenal medullary lineages, which subsequently occupy distinct regions of the embryo, with sympathetic ganglia remaining in the dorsal region and endocrine cells moving ventrally. These BMP factors not only induce chemotactic signals that attract the precursor cells to the aorta but also promote the segregation of their daughter-cell lineages and even lay down a chemical trail that leads the adrenal medullary cells to their destination. Each of these BMP functions plays out in a context-dependent manner, highlighting the importance of the in vivo environment to the fate determination and morphogenesis of NCCs.

Projection of certain Sympathetic Neurons follows Patterns established by Blood Vessels

The vascular system instructs sympathetic neural cell behavior later in development as well. The projection of certain sympathetic neurons follows patterns established by blood vessels and mediated by ligands, including artemin and endothelin. Neurons from the superior cervical ganglia, for example, project along the external carotid artery. The smooth muscle cells (pericytes) that ensheathe this blood vessel express endothelin-converting enzyme, which converts inactive precursor molecules to the bioactive form of endothelin. Intriguingly, in the head region, these smooth muscle cells also derive from NCCs, illustrating how different neural crest lineages   interact in complex ways   to instruct the formation of complex multitissue systems.

Schwann Cells are Glial Ensheathing Cells that Cover the Entire Length of Peripheral Nervous System

Neural crest–derived cells can also influence the vasculature. Schwann cells are glial ensheathing cells that cover the entire length of every neuron in the peripheral nervous system. These neurons in turn project to every organ system, including the blood vessels, making Schwann cells the most widely distributed form of neural crest–derived cell in the body. In addition to their function in neural myelination, Schwann cells also play a role in vascular patterning. In the skin of embryonic mice at around day 15 of development, sensory neurons run parallel with arterial, but not venous, vessels during the period when the vascular network is forming. This nerve-artery association is mediated by the chemokine SDF1 (CXCL12) secreted by Schwann cells associated with sensory neurons.

Schwann Cells can Induce Differentiation of Cells Outside the Neural Crest Lineage

In the adult body as well, Schwann cells can induce differentiation of cells outside the neural crest lineage. Researchers found that sympathetic nonmyelinating Schwann cells invade the bone marrow and serve as a component of the hematopoietic stem cell niche. An active form of transforming growth factor–β produced by these cells maintains these stem cells in a quiescent state. Future investigations should reveal how the balance between this Schwann cell–mediated dormancy and stem cell activation is regulated, particularly because it is known that the latter follows an oscillating circadian pattern, itself under the control of the sympathetic nervous system.

Interactive Migration in the Developing Enteric Nervous System

The enteric nervous system, which lines the entire gut and develops a wide range of independent functional capabilities, is also born from a migratory population of NCCs in the foregut. These enteric neural crest cells (ENCCs) colonize the full length of the intestine. Their migration has always been thought to closely track that of the gut wall, and when the process fails, resulting in Hirschsprung disease (aganglionosis of the gut), this absence of enteric neurons is usually observed in the distal intestine, as would be expected if ENCCs followed a purely linear course. In some rare and puzzling cases, however, patients exhibit “skip segments” in which partially innervated regions are found within otherwise aganglionic distal gut, seeming to defy the conventional model of Hirschsprung etiology in which NCCs simply fail to complete their journey down the intestinal trail

Control and Dysregulation of Schwann Cell Plasticity

Neural crest–derived cells are remarkable not only for their migratory capabilities; recent evidence has shown that they are capable of considerable plasticity as well. During early neurodevelopment, Schwann cell precursors associate closely with projecting neurites, which they support through trophic interactions. Such interactions are also critical for subsequent Schwann cell differentiation and the maintenance of the mature cell state. In the adult, Schwann cells dedifferentiate in response to injury, reverting to the precursor state to promote axon regeneration and remyelination.

As indicated from these studies, neural crest–derived glial cells possess a latent form of multipotency that is ordinarily suppressed by environmental cues, such as contact with neurons, but that can be activated in response to stimuli such as nerve injury and infection. Numerous forms of tissue stem cell–like cells have been identified in adult tissues, including skin, bone marrow, cornea, dental pulp, facial palate, and the nervous system, and several lines of evidence suggest that these cells, even those present in the same tissue, may have multiple distinct cellular origins. Given the widespread distribution and differentiative plasticity of Schwann cells, we may need to reexamine the possible contribution of reprogrammed Schwann cells to stem cell–like cell populations in various tissues.

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