Neural Crest Cells and Their Derivatives

Neural crest cells constitute a pluripotent embryonic cell population that appears only transiently during development. Neural crest cells are defined by their origins at the lateral borders of the forming neural tube, by their stem-cell-like properties, and by their ability to migrate over long distances along invariant pathways through the embryo. After being specified in the dorsal neural tube epithelium, pre-migratory neural crest cells undergo an epithelio-mesenchymal transition. Such cells detach from the neural tube epithelium and start to colonize specific target sites within the embryo as undifferentiated, but not entirely uncommitted neural crest cells, where they give rise to all major components of the peripheral nervous system (Fig. 3), i.e., primary sensory neurons, multipolar neurons of the sympathetic and parasympathetic ganglia, enteric nervous system, Schwann cell glia along peripheral nerves, and satellite glia within peripheral ganglia, as well as cutaneous mechanoreceptors (Merkel cells). Furthermore, neural crest cells contribute to the formation of the cardiac outflow tract, to facial cartilage and bone, and to the melanocyte lineage (Anderson et al. 1997; Le Douarin and Kalcheim 1999; Halata et al. 2003; Szeder et al. 2003).

On a cellular level, development of neural crest cells and their derivatives involves processes like proliferation, survival, migration, and cell fate determination and differentiation. Neural crest development can be subdivided into three major phases: (1) specification of neural crest cell identity within the neural epithelium, (2) epithelio-mesenchymal transition, delamination, and directed migration of undifferentiated neural crest cells to their targets, and (3) target-site-specific differentiation into final cell types. Over the past fifteen years, key molecules in the control of neural crest cell development have been discovered (Anderson et al. 1997; Le Douarin and Kalcheim 1999; Meulemans and Bronner-Fraser 2004).

It has become clear from classical experimental studies carried out in different species, that signals from surrounding, nonneural tissues as well as cell-intrinsic

Fig. 3 Schematic cross-section through the trunk region of a embryo, showing major subpopulations of developing neural crest cells and their characteristic migratory pathways (left side, red). On the right side (green) adult derivatives of the neural crest are represented. (Modified after Carlson, Patten's Foundations of Embryology, 6th edition 1996, McGraw-Hill, New York)

Fig. 3 Schematic cross-section through the trunk region of a embryo, showing major subpopulations of developing neural crest cells and their characteristic migratory pathways (left side, red). On the right side (green) adult derivatives of the neural crest are represented. (Modified after Carlson, Patten's Foundations of Embryology, 6th edition 1996, McGraw-Hill, New York)

mechanisms are involved in the induction of neural crest cells at the dorso-lateral borders of the neural tube epithelium (Knecht and Bronner-Fraser 2002; Barem-baum and Bronner-Fraser 2005). Nonneural ectoderm when juxtaposed to neural plate tissue can induce neural crest cells. Even nonaxial, lateral mesoderm, when cocultured with neural plates has been shown to elicit expression of some neural crest markers (Moury and Jacobson 1990; Selleck and Bronner-Fraser 1995; Marchant et al. 1998). Several recent studies have demonstrated inductive activity of these tissues to be conferred by signaling molecules of the Wnt, BMP, and FGF family. Probably the best experimental evidence for participation of extrinsic signals in this process comes from recent studies in chicken: addition of Wntl-conditioned medium to naïve intermediate neural plate tissue is sufficient to induce the formation of neural crest cells in vitro (Garcia-Castro et al. 2002).

Furthermore, intermediate neural plates can give rise to neural crest in the absence of nonneural ectoderm, when BMPs have been added to the in vitro culture (Liem et al. 1995; Liem et al. 1997; Lee and Jessell 1999). Mice with a compound mutation of the Wnt1 and Wnt3a genes show defects in the early steps of neural crest formation as well, further supporting a critical role of this signaling pathway in this process (Ikeya et al. 1997). In addition to outside signals, several transcription fac tors have been demonstrated to control neural crest induction cell-autonomously. Sox9, a member of the SoxE subgroup of HMG-box containing transcription factors and the winged-helix transcription factor FoxD3 can both induce phenotypic properties of neural crest cells when overexpressed in the chicken neural tube, and loss-of-function analysis of Sox9 in Xenopus embryos further suggests that Sox9 is required for the generation of the cranial neural crest (Dottori et al. 2001; Kos et al. 2001; Spokony et al. 2002; Cheung and Briscoe 2003). Since neither factor is sufficient to promote efficient epithelio-mesenchymal transition and delamina-tion of neural crest cells by itself when overexpressed in the neural tube, it has been speculated that both events are independently controlled (Dottori et al. 2001; Cheung and Briscoe 2003). Indeed, in a very recent, elegant study James Briscoe's group (NIMR, London) has shown that the coordinated activities of Sox9, FoxD3 and another zinc finger transcription factor, slug/snail, which was previously implicated in the control of neural crest cell migratory behavior (Nieto et al. 1994; LaBonne and Bronner-Fraser 2000; del Barrio and Nieto 2002), are required for the manifestation of all principal transcriptional and morphological characteristics of neural crest cells (Cheung et al. 2005).

Peripheral Neuropathy Natural Treatment Options

Peripheral Neuropathy Natural Treatment Options

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