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PubMed2003

The protooncogene c-myc is an essential regulator of neural crest formation in xenopus.

The neural crest, a population of multipotent progenitor cells, is a defining feature of vertebrate embryos. Neural crest precursor cells arise at the neural plate border in response to inductive signals, but much remains to be learned about the molecular mechanisms underlying their induction. Here we show that the protooncogene c-Myc is an essential early regulator of neural crest cell formation in Xenopus. c-myc is localized at the neural plate border prior to the expression of early neural crest markers, such as slug. A morpholino-mediated "knockdown" of c-Myc protein results in the absence of neural crest precursor cells and a resultant loss of neural crest derivatives. These effects are not dependent upon changes in cell proliferation or cell death. Instead, our findings reveal an important and unexpected role for c-Myc in the specification of cell fates in the early ectoderm.

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PubMed1992

Identification of early neurogenic cells in the neural crest lineage.

Pluripotent neural crest cells are restricted progressively during development. The sequence of restrictions and the time(s) in early development at which such restrictions are imposed on crest-derived cells are largely unknown. We have used a human autoantibody (Anti-Hu) to characterize neurogenic populations of avian neural crest-derived cells. Anti-Hu binds specifically to neurons and neuroendocrine cells in older (greater than E4) quail embryos. Early in development, Anti-Hu also binds a subpopulation of neural crest-derived cells that lack neuronal morphology and do not express other neuronal traits. These cells may represent a putative neurogenic precursor subpopulation within the early crest cell lineage. To test this hypothesis, we have characterized Anti-Hu immunoreactivity within crest-derived populations known to have, or to lack, the ability to give rise to new neurons. We report that the presence of Anti-Hu+ nonneuronal cells is correlated with the neurogenic ability of a given cell population. Moreover, Anti-Hu+ nonneuronal cells are transient and appear to be replaced by Anti-Hu+ neuronal cells. We conclude that Anti-Hu is a very early indicator of neurogenesis among crest-derived cells and that Anti-Hu+ nonneuronal cells are either neurogenic precursors or immature neurons.

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PubMed1987

Behavior of neural crest cells on embryonic basal laminae.

Neural crest cells separate from the neural epithelium in a region devoid of a basal lamina and migrate along pathways bordered by intact basal laminae. The distribution of basal laminae suggests that they might have an important role in the morphogenesis of the neural crest by acting as a barrier to migration. The experiments reported here have tested directly whether neural crest cells can penetrate a basal lamina. Isolated neural tubes, neural crest cells cultured for 24 hr, or pigmented neural crest cells were explanted onto human placental amnions from which the epithelium had been removed to expose the basal lamina. In no case did neural crest cells or crest derivatives penetrate the basal lamina to invade the underlying stroma. If crest cells were grown on the stromal side of the amnion, they invaded the connective tissue. Pigmented neural crest derivative and [3H]thymidine-labeled nonpigmented crest cells were also confronted with chick embryonic basal laminae by grafting the cells into the lumen of the neural tube at the axial levels where host crest migration had commenced. Most of the grafted cells invaded the neural epithelium and accumulated after 24 hr at the basal surface of the neural tube. A few crest cells escaped through the dorsal surface of the neural tube and entered the overlying ectoderm, presumably through the wound created during the grafting procedure. Some of these grafted cells, located initially by light microscopy, were examined at the higher magnification and resolution offered by the transmission electron microscope to determine the relationship of the grafted cells to the basal lamina. In 50% (14 total) of the cases, the crest cells never reached the basal lamina of the neural tube, but were trapped by cell junctions between the neural epithelial cells. Of the remaining grafted cells that were relocated in the TEM (50%, total 15) all were spread on the basal lamina, but were not seen penetrating it. Likewise, in the three cases where crest cells were found in the epidermal ectoderm, all were in contact with the basal lamina of the ectoderm but did not have any processes extending through it. In three cases, at the level of the light microscope, crest cells were found to extend through the basal surface of the neural tube. In all these instances, the cells followed the dorsal root nerve exiting through a region of the neural tube that is devoid of a basal lamina.(ABSTRACT TRUNCATED AT 400 WORDS)

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PubMed2006

Antagonistic roles of full-length N-cadherin and its soluble BMP cleavage product in neural crest delamination.

During neural crest ontogeny, an epithelial to mesenchymal transition is necessary for cell emigration from the dorsal neural tube. This process is likely to involve a network of gene activities, which remain largely unexplored. We demonstrate that N-cadherin inhibits the onset of crest delamination both by a cell adhesion-dependent mechanism and by repressing canonical Wnt signaling previously found to be necessary for crest delamination by acting downstream of BMP4. Furthermore, N-cadherin protein, but not mRNA, is normally downregulated along the dorsal tube in association with the onset of crest delamination, and we find that this process is triggered by BMP4. BMP4 stimulates cleavage of N-cadherin into a soluble cytoplasmic fragment via an ADAM10-dependent mechanism. Intriguingly, when overexpressed, the cytoplasmic N-cadherin fragment translocates into the nucleus, stimulates cyclin D1 transcription and crest delamination, while enhancing transcription of beta-catenin. CTF2 also rescues the mesenchymal phenotype of crest cells in ADAM10-inhibited neural primordia. Hence, by promoting its cleavage, BMP4 converts N-cadherin inhibition into an activity that is likely to participate, along with canonical Wnt signaling, in the stimulation of neural crest emigration.

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PubMed1993

Neurotrophin-3 affects proliferation and differentiation of distinct neural crest cells and is present in the early neural tube of avian embryos.

Neurotrophin-3 is mitogenic for cultured quail neural crest cells (Kalcheim et al., 1992, Proc. Natl. Acad. Sci. USA 89:1661-1665). We now report that neurotrophin-3 also influences the survival and/or differentiation of a subset of postmitotic neural crest precursors into neurons, provided these progenitors are grown on a cellular substrate. When cultured for 1 day on monolayers of NT-3-producing, chinese hamster ovary cells, 59% of the neural crest clusters growing on the transfected line revealed the presence of intense neuronal outgrowth, compared to 25% of that in controls. Moreover, dissociated neural crest cells grown for 20 h on top of mesodermal cells in the presence of various concentrations of purified recombinant neurotrophin-3 displayed a dose-dependent increase in neuronal number. Localization experiments using specific polyclonal antibodies, revealed that neurotrophin-3 is confined to neuroepithelial cells of quail neural tubes in situ on E2 and E3, and to E2 neural tubes grown in culture for 24 h. At this stage, neural crest cells and somites were negative. At later stages, staining was likewise apparent in peripheral nerves and dorsal root ganglia. We, therefore, propose that NT-3, a factor that is expressed in the early avian central nervous system, has multiple effects both on the proliferation and differentiation of distinct neural crest cells, which depend on the state of commitment of the responsive progenitors.

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PubMed2002

Aortic arch and pharyngeal phenotype in the absence of BMP-dependent neural crest in the mouse.

Neural crest cells are essential for proper development of a variety of tissues and structures, including peripheral and autonomic nervous systems, facial skeleton, aortic arches and pharyngeal glands like the thymus and parathyroids. Previous work has shown that bone morphogenic protein (BMP) signalling is required for the production of migratory neural crest cells that contribute to the neurogenic and skeletogenic lineages. We show here that BMP-dependent neural crest cells are also required for development of the embryonic aortic arches and pharynx-derived glands. Blocking formation or migration of this crest cell population from the caudal hindbrain resulted in strong phenotypes in the cardiac outflow tract and the thymus. Thymic aplasia or hypoplasia occurs despite uncompromised gene induction in the pharyngeal endoderm. In addition, when hypoplastic thymic tissue is found, it is ectopically located, but functional in thymopoiesis. Our data indicate that thymic phenotypes produced by neural crest deficits result from aberrant formation of pharyngeal pouches and impaired migration of thymic primordia because the mesenchymal content in the branchial arches is below a threshold level.

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PubMed2003

Interplay between Notch signaling and the homeoprotein Xiro1 is required for neural crest induction in Xenopus embryos.

The neural crest is a population of cells that originates at the interface between the neural plate and non-neural ectoderm. Here, we have analyzed the role that Notch and the homeoprotein Xiro1 play in the specification of the neural crest. We show that Xiro1, Notch and the Notch target gene Hairy2A are all expressed in the neural crest territory, whereas the Notch ligands Delta 1 and Serrate are expressed in the cells that surround the prospective crest cells. We have used inducible dominant-negative and activator constructs of both Notch signaling components and Xiro1 to analyze the role of these factors in neural crest specification without interfering with mesodermal or neural plate development. Activation of Xiro1 or Notch signaling led to an enlargement of the neural crest territory, whereas blocking their activity inhibited the expression of neural crest markers. It is known that BMPs are involved in the induction of the neural crest and, thus, we assessed whether these two elements might influence the expression of Bmp4. Activation of Xiro1 and of Notch signaling upregulated Hairy2A and inhibited Bmp4 transcription during neural crest specification. These results, in conjunction with data from rescue experiments, allow us to propose a model wherein Xiro1 lies upstream of the cascade regulating Delta 1 transcription. At the early gastrula stage, the coordinated action of Xiro1, as a positive regulator, and Snail, as a repressor, restricts the expression of Delta 1 at the border of the neural crest territory. At the late gastrula stage, Delta 1 interacts with Notch to activate Hairy2A in the region of the neural fold. Subsequently, Hairy2A acts as a repressor of Bmp4 transcription, ensuring that levels of Bmp4 optimal for the specification of the neural plate border are attained in this region. Finally, the activity of additional signals (WNTs, FGF and retinoic acid) in this newly defined domain induces the production of neural crest cells. These data also highlight the different roles played by BMP in neural crest specification in chick and Xenopus or zebrafish embryos.

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PubMed2004

Neural crest and the origin of ectomesenchyme: neural fold heterogeneity suggests an alternative hypothesis.

The striking similarity between mesodermally derived fibroblasts and ectomesenchyme cells, which are thought to be derivatives of the neural crest, has long been a source of interest and controversy. In mice, the gene encoding the alpha subunit of the platelet-derived growth factor receptor (PDGFRalpha) is expressed both by mesodermally derived mesenchymal cells and by ectomesenchyme. Whole-mount immunostaining previously revealed that PDGFRalpha is present in the cephalic neural fold epithelium of early murine embryos (Takakura et al. [1997] J Histochem Cytochem 45:883-893). We now show that, within the neural fold, a sharp boundary exists between E-cadherin-expressing non-neural epithelium and the neural epithelium of the dorsal ridge. In addition, we found that cells coexpressing E-cadherin and PDGFRalpha are present in the non-neural epithelium of the neural folds. These observations raise the possibility that at least some PDGFRalpha(+) ectomesenchyme originates from the lateral non-neural domain of neural fold epithelium. This inference is consistent with previous reports (Nichols [ 1981] J Embryol Exp Morphol 64:105-120; Nichols [ 1986] Am J Anat 176:221-231) that mesenchymal cells emerge precociously from an epithelial neural fold domain resembling the primitive streak in the early embryonic epiblast. Therefore, we propose the name "metablast" for this non-neural epithelial domain to indicate that it is the site of a delayed local delamination of mesenchyme similar to involution of mesoderm during gastrulation. We further propose the testable hypothesis that neural crest and ectomesenchyme are developmentally distinct progenitor populations and that at least some ectomesenchyme is metablast-derived rather than neural crest-derived tissue. Developmental Dynamics 229:118-130, 2004.

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PubMed1996

High glucose concentration inhibits migration of rat cranial neural crest cells in vitro.

Cranial neural crest cells give rise to a large part of the facial structures, and disturbed development of these cells may therefore cause congenital malformations affecting the head and face. We studied the effects of increased glucose concentration on the migration and development of cranial neural crest cells, maintained in vitro for 48 h. Pre-migratory cranial neural crest cells were removed from embryos of normal and diabetic rats on gestational day 9. After 24 h in 10 mmol/l glucose the cells were exposed to glucose concentrations of 10, 30, or 50 mmol/l for another 24 h. The cultures were photographed at 24 h and 48 h in a phase-contrast microscope to evaluate cell morphology, cell number, and cell migration. Exposure to 50 mmol/l glucose reduced the total number of neural crest cells, their mean migratory distance and migratory area expansion compared to cells cultured in 10 mmol/l glucose. To investigate the effect of antioxidant agents, high glucose cultures were studied after addition of N-acetylcysteine (NAC), or superoxide dismutase (SOD). Addition of NAC diminished the inhibitory effect of high glucose, whereas SOD did not offer any improvement in cell development. Neural crest cell culture from embryos of diabetic rats showed reduced cell migration in vitro at all glucose concentrations compared to normal cells. In addition, the cells from embryos of diabetic rats showed reduced migratory area expansion after culture in the basal 10 mmol/l glucose concentration, indicating that maternal diabetes permanently influences the future development of premigratory cranial neural crest cells. These findings indicate that high glucose concentration inhibits cranial neural crest development in vitro, and that antioxidant therapy may diminish this inhibition. Free radical oxygen species may be involved in the induction of malformations and antioxidants may therefore have a role in future attempts to block the teratogenic effects of diabetic pregnancy.

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PubMed1997

Timing and pattern of cell fate restrictions in the neural crest lineage.

The trunk neural crest of vertebrate embryos is a transient collection of precursor cells present along the dorsal aspect of the neural tube. These cells migrate on two distinct pathways and give rise to specific derivatives in precise embryonic locations. One group of crest cells migrates early on a ventral pathway and generates neurons and glial cells. A later-dispersing group migrates laterally and gives rise to melanocytes in the skin. These observations raise the possibility that the appearance of distinct derivatives in different embryonic locations is a consequence of lineage restrictions specified before or soon after the onset of neural crest cell migration. To test this notion, we have assessed when and in what order distinct cell fates are specified during neural crest development. We determined the proportions of different types of precursor cells in cultured neural crest populations immediately after emergence from the neural tube and at intervals as development proceeds. We found that the initial neural crest population was a heterogeneous mixture of precursors almost half of which generated single-phenotype clones. Distinct neurogenic and melanogenic sublineages were also present in the outgrowth population almost immediately, but melanogenic precursors dispersed from the neural tube only after many neurogenic precursors had already done so. A discrete fate-restricted neuronal precursor population was distinguished before entirely separate fate-restricted melanocyte and glial precursor populations were present, and well before initial neuronal differentiation. Taken together, our results demonstrate that lineage-restricted subpopulations constitute a major portion of the initial neural crest population and that neural crest diversification occurs well before overt differentiation by the asynchronous restriction of distinct cell fates. Thus, the different morphogenetic and differentiative behavior of neural crest subsets in vivo may result from earlier cell fate-specification events that generate developmentally distinct subpopulations that respond differentially to environmental cues.

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PubMed1994

Retinoic acid selectively promotes the survival and proliferation of neurogenic precursors in cultured neural crest cell populations.

The neural crest produces both neuronal and nonneuronal derivatives in response to a variety of environmental cues. Here, we have analyzed the effects of retinoic acid on the differentiative behavior of quail trunk neural crest cells in vitro. We show that retinoic acid selectively increases neurogenesis in cultured neural crest cell populations, probably by promoting the survival and stimulating the proliferation of neuronal precursors. Our results suggest that neural crest-derived neurogenic precursors are specific targets for retinoic acid in vitro and raise the possibility that retinoic acid promotes the generation of peripheral neurons in vivo.

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PubMed1998

Inhibitory interactions in the patterning of trunk neural crest migration.

In avian embryos, trunk neural crest migrate segmentally through the somites, entering the rostral but not caudal somitic sclerotome. Inhibitory molecules in the caudal somite could prohibit entry of neural crest caudally, and thus restrict cell migration to rostral somite territories. Two sets of cues, peanut agglutinin (PNA) binding glycoproteins and members of the Eph family of receptor tyrosine kinases (RTKs) and their ligands appear to play this role in segmenting cell migration. Addition of exogenous PNA to neural crest migrating in trunk explants disrupts the normal segmental pattern of migration; neural crest travel in rostral and caudal regions of the somites. Members of the Eph family display the correct spatiotemporal localization to influence neural crest migration; the RTK EphB3 is expressed by neural crest, whereas the transmembrane ligand ephrin-B1 is expressed by caudal sclerotomal cells. Exogenous ephrin-B1 added to neural crest migrating in trunk explants also specifically disrupts the segmental organization of neural crest migration. Isolated neural crest avoid lanes containing ephrin-B1 in vitro; this avoidance is abolished by addition of soluble ligand. Time-lapse imaging reveals that neural crest exhibit a typical collapse response followed by process retraction upon encountering ligand. The results of these studies implicate PNA-binding glycoproteins and Eph family members in sculpting the migratory patterns of neural precursors in the peripheral nervous system.

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PubMed2000

Snail-related transcriptional repressors are required in Xenopus for both the induction of the neural crest and its subsequent migration.

The neural crest is a transient population of precursor cells that arises at the border between the neural plate and prospective epidermis in vertebrate embryos. The earliest known response to neural-crest-inducing signals is the expression of the zinc-finger transcription factors slug and snail. Although it is widely believed that these transcription factors play an essential role in neural crest development, relatively little is understood about their mechanism of action during this process. We have previously shown that overexpression of XSlug leads to expanded expression of neural crest markers and an excess of at least one neural crest derivative, melanocytes. In order to further investigate XSlug function, we overexpressed mutant constructs in which the DNA-binding domain was fused to either the activation domain from Gal4 or the repressor domain from Drosophila Engrailed. The Engrailed repressor fusion was found to mimic the effects of wild-type XSlug, indicating that XSlug functions as a transcriptional repressor during neural crest formation. In contrast, overexpression of either the activation domain fusion or the DNA-binding domain alone was found to inhibit XSlug function. Using a hormone-inducible inhibitory mutant, we show that inhibition of XSlug function at early stages prevents the formation of neural crest precursors, while inhibition at later stages interferes with neural crest migration, demonstrating for the first time that this transcriptional repressor is required during multiple stages of neural crest development.

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PubMed1983

Identification of nerve growth factor receptors in primary cultures of chick neural crest cells.

Primary cultures of chick neural crest cells obtained from explanted neural tubes have binding sites for radioiodinated nerve growth factor ([125I]NGF) but not for radioiodinated epidermal growth factor ([125I]EGF). The binding of [125I]NGF was shown to be a specific and saturable process with a high affinity (Kd = 0.3 nM) for the ligand. Despite the expression of these NGF binding sites, incubation of the neural crest cultures with nerve growth factor did not induce neurite outgrowth; no morphological alterations were observed. This was not due to an inability of the cells to express a neuronal phenotype, since the neural crest cells spontaneously differentiated into neurite-bearing cells. However, the nerve growth factor binding sites do appear to be functional receptors, since nerve growth factor could produce a modest induction of ornithine decarboxylase. The quantity of nerve growth factor binding sites seemed to be independent of the phenotype expressed by the neural crest cells, since both pigmented cells and neuron-like neural crest cells exhibited binding. These findings suggest that the differentiation of neural crest cells into mature nerve growth factor-responsive neurons may involve the coupling of nerve growth factor receptors to cellular responses important in the expression of the neuronal phenotype.

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PubMed1995

Rhombomeric origin and rostrocaudal reassortment of neural crest cells revealed by intravital microscopy.

Neural crest cell migration in the hindbrain is segmental, with prominent streams of migrating cells adjacent to rhombomeres (r) r2, r4 and r6, but not r3 or r5. This migratory pattern cannot be explained by the failure of r3 and r5 to produce neural crest, since focal injections of the lipophilic dye, DiI, into the neural folds clearly demonstrate that all rhombomeres produce neural crest cells. Here, we examine the dynamics of hindbrain neural crest cell emigration and movement by iontophoretically injecting DiI into small numbers of cells. The intensely labeled cells and their progeny were repeatedly imaged using low-light-level epifluorescence microscopy, permitting their movement to be followed in living embryos over time. These intravital images definitively show that neural crest cells move both rostrally and caudally from r3 and r5 to emerge as a part of the streams adjacent to r2, r4, and/or r6. Within the first few hours, cells labeled in r3 move within and/or along the dorsal neural tube surface, either rostrally toward the r2/3 border or caudally toward the r3/4 border. The labeled cells exit the surface of the neural tube near these borders and migrate toward the first or second branchial arches several hours after initial labeling. Focal DiI injections into r5 resulted in neural crest cell contributions to both the second and third branchial arches, again via rostrocaudal movements of the cells before migration into the periphery. These results demonstrate conclusively that all rhombomeres give rise to neural crest cells, and that rostrocaudal rearrangement of the cells contributes to the segmental migration of neural crest cells adjacent to r2, r4, and r6. Furthermore, it appears that there are consistent exit points of neural crest cell emigration; for example, cells arising from r3 emigrate almost exclusively from the rostral or caudal borders of that rhombomere.

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PubMed1996

Spatiotemporally exact cDNA libraries from quail embryos: a resource for studying neural crest development and neurocristopathies.

The neural crest is of fundamental importance in the developments of the head and peripheral nervous system, in the evolution of the vertebrates, and clinically because it gives rise to developmental abnormalities and neoplasms in humans. We have established a resource for studying the development of the neural crest by systematically constructing cDNA libraries from spatiotemporally exact neural crest and related cell populations. Neural crest populations were obtained from vagal and thoracic axial levels and from branchial arches, at premigratory and early and late migratory stages, at localization stages, and after differentiation into dorsal root ganglion cells, Schwann cells, sympathetic neurons, adrenal medullary cells, and melanocytes. Libraries were constructed using several methods developed to approach the issue of making representative libraries from small amounts of tissue. The fidelity and usefulness of the libraries were tested, and this revealed that they expressed a variety of sequences such as integrins, CAMs, growth factors and their receptors, protein-tyrosine kinases, and phosphatases. Differential display also revealed a unique combination of cDNA species. We then selected libraries spatiotemporally appropriate for epithelium-mesenchyme transformation and probed for TGF-beta-related sequences. As anticipated, we confirmed the presence of TGF-beta 2 and dorsalin-1 but could not detect TGF-beta 1. We also revealed new expression sites, defined by the origin of the libraries, of receptors known to be expressed elsewhere (Tsk 7l; TBRII). We anticipate that this collection of cDNA libraries will be of use in studying normal and abnormal neural crest development, by both homology searches and differential expression approaches, with spatiotemporal expression information being inherent in the initial screen.

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PubMed1993

Cell and molecular biology of neural crest cell lineage diversification.

Neural crest cells are multipotent progenitor cells, but it is not understood how these cells generate their diverse differentiated progeny. This review considers the issues of whether neural crest cells self-renew, whether they generate partially committed intermediate progenitors, and how the local embryonic environment may act to control this diversification process. Novel molecular markers for neural crest cells are also discussed.

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PubMed1983

Neural crest ablation and limb morphogenesis.

Left caudal neural crest was ablated by diathermy in 2-day-old chick embryos, to injure the region of sensory sciatic innervation before the appearance of the hind-limb bud. Embryos were fixed immediately, 24 hr and 14 days later, for examination of the effects of the ablation upon neural crest, neural tube, somitic mesoderm, and subsequent limb development. All embryos examined immediately and at 24 hr after ablation showed damage to the left neural crest, but the injury extended deeper into neural fold or tube, across the midline, and into somitic mesoderm. Of 17 chicks which survived to 16 days, 7 had gross deformity of the left leg and 10 had morphologically normal legs. Deformed chicks had a significant reduction in the mass of dorsal root ganglia on the operated side but no reduction in the area of the spinal cord. Operated chicks without limb deformities showed reduction of spinal cord but not of dorsal root ganglia. This suggests that limb morphogenesis may be quantitatively related to neural crest but not to neural tube. This possibility is considered in the light of previous publications. However, the experimental limitation of the diathermy method leaves the final conclusion open to interesting speculation and to future examination by improved experimental design.

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