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PubMed1993

Mechanisms of neural crest cell migration.

Neural crest cells are remarkable in their extensive and stereotypic patterns of migration. The pathways of neural crest migration have been documented by cell marking techniques, including interspecific neural tube grafts, immunocytochemistry and DiI-labelling. In the trunk, neural crest cells migrate dorsally under the skin or ventrally through the somites, where they move in a segmental fashion through the rostral half of each sclerotome. The segmental migration of neural crest cells appears to be prescribed by the somites, perhaps by an inhibitory cue from the caudal half. Within the rostral sclerotome, neural crest cells fill the available space except for a region around the notochord, suggesting the notochord may inhibit neural crest cells in its vicinity. In the cranial region, antibody perturbation experiments suggest that multiple cell-matrix interactions are required for proper in vivo migration of neural crest cells. Neural crest cells utilize integrin receptors to bind to a number of extracellular matrix molecules. Substrate selective inhibition of neural crest cell attachment in vitro by integrin antibodies and antisense oligonucleotides has demonstrated that they possess at least three integrins, one being an alpha 1 beta 1 integrin which functions in the absence of divalent cations. Thus, neural crest cells utilize complex sets of interactions which may differ at different axial levels.

Animals↗
PubMed1986

Coexpression of somatostatin-like immunoreactivity and catecholaminergic properties in neural crest derivatives: comodulation of peptidergic and adrenergic differentiation in cultured neural crest.

In the avian embryo, somatostatin-like immunoreactivity (SLI) and adrenergic characteristics appear virtually simultaneously in the developing sympathetic nervous system and adrenal medulla. We have used double-labeling techniques to show that both properties coexist in the same cells. In the quail, not only do all somatostatin-containing cells in the adrenosympathetic system exhibit tyrosine hydroxylase immunoreactivity and possess catecholamines (CA), but this coexistence of the peptidergic and adrenergic phenotypes is already present very early in ontogeny. However, not all adrenergic cells express SLI. The development of sympathoadrenal precursors can be followed in vitro. Adrenergic precursor cells, obtained from the migrating neural crest, differentiate in culture into neuron-like cells that contain SLI and CA. This coexpression can be regulated by the same factors. For instance, corticosterone and progesterone increase SLI content and CA production in the neural crest cell cultures. The ontogeny of the autonomic lineage is discussed in the light of these results.

Adrenal Medulla↗
PubMed2006

Frizzled7 mediates canonical Wnt signaling in neural crest induction.

The neural crest is a multipotent cell population that migrates from the dorsal edge of the neural tube to various parts of the embryo where it differentiates into a remarkable variety of different cell types. Initial induction of neural crest is mediated by a combination of BMP, Wnt, FGF, Retinoic acid and Notch/Delta signaling. The two-signal model for neural crest induction suggests that BMP signaling induces the competence to become neural crest. The second signal involves Wnt acting through the canonical pathway and leads to expression of neural crest markers such as slug. Wnt signals from the neural plate, non-neural ectoderm and paraxial mesoderm have all been suggested to play a role in neural crest induction. We show that Xenopus frizzled7 (Xfz7) is expressed in the dorsal ectoderm including early neural crest progenitors and is a key mediator of the Wnt inductive signal. We demonstrate that Xfz7 expression is induced in response to a BMP antagonist, noggin, and that Xfz7 can induce neural crest specific genes in noggin-treated ectodermal explants (animal caps). Morpholino-mediated or dominant negative inhibition of Xfz7 inhibits Wnt induced Xslug expression in the animal cap assay and in the whole embryo leading to a loss of neural crest derived pigment cells. Full-length Xfz7 rescues the morpholino-induced phenotype, as does activated beta-catenin, suggesting that Xfz7 is signaling through the canonical pathway. We therefore demonstrate that Xfz7 is regulated by BMP antagonism and is required for neural crest induction by Wnt in the developing vertebrate embryo.

Animals↗
PubMed2000

Noelin-1 is a secreted glycoprotein involved in generation of the neural crest.

The vertebrate neural crest arises at the border of the neural plate during early stages of nervous system development; however, little is known about the molecular mechanisms underlying neural crest formation. Here we identify a secreted protein, Noelin-1, which has the ability to prolong neural crest production. Noelin-1 messenger RNA is expressed in a graded pattern in the closing neural tube. It subsequently becomes restricted to the dorsal neural folds and migrating neural crest. Over expression of Noelin-1 using recombinant retroviruses causes an excess of neural crest emigration and extends the time that the neural tube is competent to generate as well as regenerate neural crest cells. These results support an important role for Noelin-1 in regulating the production of neural crest cells by the neural tube.

Amino Acid Sequence↗
PubMed2005

To proliferate or to die: role of Id3 in cell cycle progression and survival of neural crest progenitors.

The neural crest is a unique population of mitotically active, multipotent progenitors that arise at the vertebrate neural plate border. Here, we show that the helix-loop-helix transcriptional regulator Id3 has a novel role in cell cycle progression and survival of neural crest progenitors in Xenopus. Id3 is localized at the neural plate border during gastrulation and neurulation, overlapping the domain of neural crest induction. Morpholino oligonucleotide-mediated depletion of Id3 results in the absence of neural crest precursors and a resultant loss of neural crest derivatives. This appears to be mediated by cell cycle inhibition followed by cell death of the neural crest progenitor pool, rather than a cell fate switch. Conversely, overexpression of Id3 increases cell proliferation and results in expansion of the neural crest domain. Our data suggest that Id3 functions by a novel mechanism, independent of cell fate determination, to mediate the decision of neural crest precursors to proliferate or die.

Animals↗
PubMed2004

Antisense knockdown of the beta1 integrin subunit in the chicken embryo results in abnormal neural crest cell development.

Neural crest cells escape the neural tube by undergoing an epithelial to mesenchymal transition (EMT). This is followed by extensive migration along specific pathways that are lined with extracellular matrix (ECM). In this study, we have examined the roles of matrix receptors containing beta1 integrin subunits in neural crest cell morphogenesis using antisense morpholino oligos electroporated in ovo into avian neural crest cell precursors. Our results show that reduced levels of expression of beta1 integrin subunits in the dorsal neural tube results in an abnormal epithelial to mesenchymal transition. In approximately half of the experimental embryos, however, some neural crest cells filled with beta1 antisense are able to escape the neural tube and migrate ventrally, indicating that grossly normal migration of trunk neural crest cells can take place after beta1 integrin expression is reduced. This study shows the potential of this novel method for investigating the roles of genes that are required for the survival of early mouse embryos in later development events.

Animals↗
PubMed1993

Molecular regulation of neural crest development.

The neural crest is a transient embryonic structure that gives rise to a multitude of different cell types in the vertebrate. As such, it is an ideal model to study the processes of vertebrate differentiation and development. This review focuses on two major questions related to neural crest development. The first question concerns the degree and time of commitment of the neural crest cells to different cell lineages and the emerging role of the homeobox containing genes in regulating this process. Evidence from the cephalic crest suggests that the commitment process does start before the neural crest cells migrate away from the neural tube and gene ablation experiments suggest that different homeobox genes are required for the development of neural and mesenchymal tissue derivatives. However, clonal analysis of neural crest cells before migration suggests that many of the cells remain multi-potential indicating that the final determinative steps occur progressively during migration and in association with environmental influences. The second question concerns the nature of the environmental factors that determine the differentiation of neural crest cells into discrete lineages. Evidence is provided, mainly from in vitro experiments, that purified growth factors selectively promote the differentiation of neural crest cells down either sympathetic, adrenal, sensory, or melanocytic cell lineages.

Animals↗
PubMed2005

Xenopus Id3 is required downstream of Myc for the formation of multipotent neural crest progenitor cells.

Neural crest cells, a population of proliferative, migratory, tissue-invasive stem cells, are a defining feature of vertebrate embryos. These cells arise at the neural plate border during a time in development when precursors of the central nervous system and the epidermis are responding to the extracellular signals that will ultimately dictate their fates. Neural crest progenitors, by contrast, must be maintained in a multipotent state until after neural tube closure. Although the molecular mechanisms governing this process have yet to be fully elucidated, recent work has suggested that Myc functions to prevent premature cell fate decisions in neural crest forming regions of the early ectoderm. Here, we show that the small HLH protein Id3 is a Myc target that plays an essential role in the formation and maintenance of neural crest stem cells. A morpholino-mediated 'knockdown' of Id3 protein results in embryos that lack neural crest. Moreover, forced expression of Id3 maintains the expression of markers of the neural crest progenitor state beyond the time when they would normally be downregulated and blocks the differentiation of neural crest derivatives. These results shed new light on the mechanisms governing the formation and maintenance of a developmentally and clinically important cell population.

Animals↗
PubMed1993

Cell lineage analysis in neural crest ontogeny.

The neural crest is a transitory and pluripotent structure of the vertebrate embryo composed of cells endowed with developmentally regulated migratory properties. We review here a series of studies carried out both in vivo and in vitro on the ontogeny of the neural crest in the avian embryo. Through in vivo studies we established the fate map of the neural crest along the neuraxis prior to the onset of the migration and we demonstrated the crucial role played by the tissue environment in which the crest cells migrate in determining their fate. Moreover, the pathways of neural crest cell migration could also be traced by the quail-chick marker system and the use of the HNK1/NC1 monoclonal antibody (Mab). A large series of clonal cultures of isolated neural crest cells showed that, at migration time, most crest cells are pluripotent. Some, however, are already committed to a particular pathway of differentiation. The differentiation capacities of the pluripotent progenitors are highly variable from one to the other cell. Rare totipotent progenitors able to give rise to representatives of all the phenotypes (neuronal, glial, melanocytic, and mesectodermal) encountered in neural crest derivatives were also found. As a whole we propose a model according to which totipotent neural crest cells become progressively restricted (according to a stochastic rather than a sequentially ordered mechanism) in their potentialities, while they actively divide during the migration process. At the sites of gangliogenesis, selective forces allow only certain crest cells potentialities to be expressed in each type of peripheral nervous system (PNS) ganglia.

Animals↗
PubMed1989

Culture conditions affect the cholinergic development of an isolated subpopulation of chick mesencephalic neural crest cells.

Although neural crest cells are known to be very responsive to environmental cues during their development, recent evidence indicates that at least some subpopulations may be committed to a specific differentiation program prior to migration. Because the neural crest is composed of a heterogeneous mixture of cells that contributes to many vertebrate cell lineages, assessing the properties of specific subpopulations and the effect of the environment on their development has been difficult. To address this problem, we have isolated a pure subpopulation of chick mesencephalic neural crest cells by fluorescence no-flow cytometry after labeling them with monoclonal antibodies (Mabs) to a 75-kDa cell surface antigen that is associated with high affinity choline uptake. When cultures of chick mesencephalic neural crest cells are labeled with these Mabs and a fluorescent second step antibody, approximately 5% of the cells are antigen-positive (A+). After sorting, 100% of the resulting cultured mesencephalic neural crest cells are A+. The Mabs we used also label all of the neurons of the embryonic chick and quail ciliary ganglion in vivo and in vitro. We have compared the effect of various cell culture media on the isolated neural crest subpopulation and the heterogeneous chick mesencephalic neural crest from which it was derived. A+ cells were passaged and grown in a variety of media, each of which differently affected its characteristics and development. A+ cells proliferated in the presence of 15% fetal bovine serum (FBS) and high concentrations (10-15%) of chick embryo extract, but did not differentiate, although they retained basal levels of choline acetyltransferase (ChAT) activity. However, in chick serum and high (25 mM as opposed to 7 mM) K+, and heart-, iris-, or lung-conditioned medium, all of which are known to promote survival and/or cholinergic development of ciliary ganglion neurons, the cells ceased to proliferate and all of the cells in the culture became "neuron-like" within 10 days. No neuron-like cells were found in liver-, notocord-, or neural tube-conditioned media if FBS was used. When A+ cells were eliminated either by complement-mediated cytotoxicity or by laser-ablating A+ cells during no-flow cytometry, all ChAT activity was also eliminated, and no neuron-like cells or ChAT activity was found in cultures during a subsequent 3-week culture period.(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed2004

Significance of the cranial neural crest.

The cranial neural crest has long been viewed as being of particular significance. First, it has been held that the cranial neural crest has a morphogenetic role, acting to coordinate the development of the pharyngeal arches. By contrast, the trunk crest seems to play a more subservient role in terms of embryonic patterning. Second, the cranial crest not only generates neurons, glia, and melanocytes, but additionally forms skeletal derivatives (bones, cartilage, and teeth, as well as smooth muscle and connective tissue), and this potential was thought to be a unique feature of the cranial crest. Recently, however, several studies have suggested that the cranial neural crest may not be so influential in terms of patterning, nor so exceptional in the derivatives that it makes. It is now becoming clear that the morphogenesis of the pharyngeal arches is largely driven by the pharyngeal endoderm. Furthermore, it is now apparent that trunk neural crest cells have skeletal potential. However, it has now been demonstrated that a key role for the cranial neural crest streams is to organise the innervation of the hindbrain by the cranial sensory ganglia. Thus, in the past few years, our views of the significance of the cranial neural crest for head development have been altered. Developmental Dynamics 229:5-13, 2004.

Animals↗
PubMed1990

Spatiotemporal changes in HNK-1/L2 glycoconjugates on avian embryo somite and neural crest cells.

Neural crest cell migration was studied in trunks of quail and chick embryos using HNK-1 and L2 antibodies. At the intersegmental cleft, labeled crest cells were associated with the rostral wall of the somite rather than blood vessels. Migration into and through the rostral part of the sclerotomes was more rapid (40-70 microns/hr; quail) and the onset of localization was earlier (after 13-16 hr; quail) than previously supposed. Crest cells here were initially mono- to multipolar, scattered, and inconsistently oriented and formed numerous close (about 20 nm) homo- and heterotypic cell-cell contacts. In vitro models suggested that significant numbers of crest cells, however, could be unlabeled at this early phase. Somitic properties covarying with the hemisegmental pattern of crest cell immigration were investigated. Laminin distribution, although asymmetric in the somites, was not closely related to that of crest cells. Tenascin distribution matched that of crest cells, but only at the localization stage. Earlier, maximal tenascin expression occurred in the somite's caudal wall, a region avoided by crest cells. Chondroitin 6-sulfate proteoglycan expression was elevated in the caudal somite-half at the localization phase and also, at lumbar levels, at the immigration stage. This is consistent with tenascin and proteoglycan having a negative role in crest cell migration. The rostral somite-half was also labeled by HNK-1 and L2, but only in quails. This was associated with the cell surface, was transient, was stable to mild proteolysis, and was labile to cryoprocessing and lipophilic solvents. The spatial and temporal congruence with crest migration suggests that the HNK/L2 adhesion-related carbohydrate epitope on the somites indicates a molecule (possibly glycolipid) which acts via heterotypic cell-cell contacts to provide one cue in the patterned distribution of crest cells in the somites.

Animals↗
PubMed2003

lockjaw encodes a zebrafish tfap2a required for early neural crest development.

The neural crest is a uniquely vertebrate cell type that gives rise to much of the craniofacial skeleton, pigment cells and peripheral nervous system, yet its specification and diversification during embryogenesis are poorly understood. Zebrafish homozygous for the lockjaw (low) mutation show defects in all of these derivatives and we show that low (allelic with montblanc) encodes a zebrafish tfap2a, one of a small family of transcription factors implicated in epidermal and neural crest development. A point mutation in low truncates the DNA binding and dimerization domains of tfap2a, causing a loss of function. Consistent with this, injection of antisense morpholino oligonucleotides directed against splice sites in tfap2a into wild-type embryos produces a phenotype identical to low. Analysis of early ectodermal markers revealed that neural crest specification and migration are disrupted in low mutant embryos. TUNEL labeling of dying cells in mutants revealed a transient period of apoptosis in crest cells prior to and during their migration. In the cranial neural crest, gene expression in the mandibular arch is unaffected in low mutants, in contrast to the hyoid arch, which shows severe reductions in dlx2 and hoxa2 expression. Mosaic analysis, using cell transplantation, demonstrated that neural crest defects in low are cell autonomous and secondarily cause disruptions in surrounding mesoderm. These studies demonstrate that low is required for early steps in neural crest development and suggest that tfap2a is essential for the survival of a subset of neural crest derivatives.

Amino Acid Sequence↗
PubMed1995

Epithelium-mesenchyme transition during neural crest development.

The neural crest is the organ system whose presence defines vertebrates. The onset of migration of neural crest cells is an archetypal epithelium to mesenchyme transition (EMT), and this event identifies the cell lineage. Little is known yet of the establishment of the neural crest, although the zinc finger gene Slug seems to be involved in specifying EMT competence. The details, especially the temporal order of events in neural crest EMT, vary between different species and between different axial levels, but several important features have emerged from observations in situ and experiments in vitro and in vivo. EMT seems to be strongly associated with decrease in cell-cell adhesion, and particularly with loss of N-cadherin on the surface of neural crest cells at the time of onset of migration. The related adhesion molecule T-cadherin is also present, but correlated changes have not yet been described, while the unrelated adhesion molecule N-CAM also declines on neural crest cells, but with a time course unrelated to EMT. The extracellular matrix is also important: EMT-related changes in matrix receptor (i.e. integrin) activity are recorded in avian crest cells, while the nature of the matrix itself changes in urodele amphibians. Changes in cell shape and in cell motility also occur at the time of EMT, consistent with changes in the cytoskeleton. These concerted changes can be triggered by TGF-beta family growth factors, of which dorsalin-I appears particularly important. These may act through pathways involving controlled alterations in phosphorylation to effect the complex of responses that make up EMT. Although much remains to be understood, the spatiotemporal definability of this system makes it a very useful model for studying EMTs in general.

Animals↗
PubMed2003

Multipotentiality of the neural crest.

Multiple neural and non-neural cell types arise from the neural crest (NC) in vertebrate embryos. Recent work has provided evidence for multipotent stem cells and intermediate precursors in the early NC cell population as well as in various NC derivatives in embryos and even in adult. Advances have been made towards understanding how cytokines, regulatory genes and cell-cell interactions cooperate to control commitment and differentiation to pigment cells, glia and neurone subtypes. In addition, NC cell fates appeared to be unstable, as differentiated NC cells can reverse to multipotent precursors and transdifferentiate in vitro.

Animals↗
PubMed2001

Segmental organization of neural crest migration.

Avian neural crest cells migrate on precise pathways to their target areas where they form a wide variety of cellular derivatives, including neurons, glia, pigment cells and skeletal components. In one portion of their pathway, trunk neural crest cells navigate in the somitic mesoderm in a segmental fashion, invading the rostral, while avoiding the caudal, half-sclerotome. This pattern of cell migration, imposed by the somitic mesoderm, contributes to the metameric organization of the peripheral nervous system, including the sensory and sympathetic ganglia. At hindbrain levels, neural crest cells also travel from the neural tube in a segmental manner via three migratory streams of cells that lie adjacent to even-numbered rhombomeres. In this case, the adjacent mesoderm does not possess an obvious segmental organization, compared to the somitic mesoderm at trunk levels. Thus, the mechanisms by which the embryo controls segmentally-organized cell migrations have been a fascinating topic over the past several years. Here, I discuss findings from classical and recent studies that have delineated several of the tissue, cellular and molecular elements that contribute to the segmental organization of neural crest migration, primarily in the avian embryo. One common theme is that neural crest cells are prohibited from entering particular territories in the embryo due to the expression of inhibitory factors. However, permissive, migration-promoting factors may also play a key role in coordinating neural crest migration.

Animals↗
PubMed1993

Environmental influences on neural crest cell migration.

Neural crest cells migrate extensively and interact with numerous tissues and extracellular matrix components during their movement. Cell marking techniques have shown that neural crest cells in the trunk of the avian embryo migrate through the anterior, but not posterior, half of each sclerotome and avoid the region around the notochord. A possible mechanism to account for this migratory pattern is that neural crest cells may be inhibited from entering the posterior sclerotome and the perinotochordal space. Thus, interactions with other tissue may prescribe the pattern of neural crest cell migration in the trunk. In contrast, interactions between neural crest cells and the extracellular matrix may mediate the primary interactions controlling neural crest cells migration in the head region.

Animals↗
PubMed1994

Rhombomere rotation reveals that multiple mechanisms contribute to the segmental pattern of hindbrain neural crest migration.

Hindbrain neural crest cells adjacent to rhombomeres 2 (r2), r4 and r6 migrate in a segmental pattern, toward the first, second and third branchial arches, respectively. Although all rhombomeres generate neural crest cells, those arising from r3 and r5 deviate rostrally and caudally (J. Sechrist, G. Serbedzija, T. Scherson, S. Fraser and M. Bronner-Fraser (1993) Development 118, 691-703). We have altered the rostrocaudal positions of the cranial neural tube, adjacent ectoderm/mesoderm or presumptive otic vesicle to examine tissue influences on this segmental migratory pattern. After neural tube rotation, labeled neural crest cells follow pathways generally appropriate for their new position after grafting. For example, when r3 and r4 were transposed, labeled r3 cells migrated laterally to the second branchial arch whereas labeled r4 cells primarily deviated caudally toward the second arch, with some cells moving rostrally toward the first. In contrast to r4 neural crest cells, transposed r3 cells leave the neural tube surface in a polarized manner, near the r3/4 border. Surprisingly, some labeled neural crest cells moved directionally toward small ectopic otic vesicles that often formed in the ectoderm adjacent to grafted r4. Similarly, they moved toward grafted or displaced otic vesicles. In contrast, surgical manipulation of the mesoderm adjacent to r3 and r4 had no apparent effects. Our results offer evidence that neural crest cells migrate directionally toward the otic vesicle, either by selective attraction or pathway-derived cues.

Animals↗