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PubMed1996

The chinless mutation and neural crest cell interactions in zebrafish jaw development.

During vertebrate development, neural crest cells are thought to pattern many aspects of head organization, including the segmented skeleton and musculature of the jaw and gills. Here we describe mutations at the gene chinless, chn, that disrupt the skeletal fates of neural crest cells in the head of the zebrafish and their interactions with muscle precursors. chn mutants lack neural-crest-derived cartilage and mesoderm-derived muscles in all seven pharyngeal arches. Fate mapping and gene expression studies demonstrate the presence of both undifferentiated cartilage and muscle precursors in mutants. However, chn blocks differentiation directly in neural crest, and not in mesoderm, as revealed by mosaic analyses. Neural crest cells taken from wild-type donor embryos can form cartilage when transplanted into chn mutant hosts and rescue some of the patterning defects of mutant pharyngeal arches. In these cases, cartilage only forms if neural crest is transplanted at least one hour before its migration, suggesting that interactions occur transiently in early jaw precursors. In contrast, transplanted cells in paraxial mesoderm behave according to the host genotype; mutant cells form jaw muscles in a wild-type environment. These results suggest that chn is required for the development of pharyngeal cartilages from cranial neural crest cells and subsequent crest signals that pattern mesodermally derived myocytes.

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PubMed1983

Serotoninergic differentiation of quail neural crest cells in vitro.

The in vitro differentiation of quail neural crest cells into serotoninergic neurons is reported. Serotoninergic neurons were identified by two independent methods, formaldehyde-induced histofluorescence and indirect staining with antiserotonin antibodies. Serotonin-positive cells first appeared on the third day in culture, simultaneously, or slightly prior to the first pigmented cells and adrenergic neurons. Comparable numbers of serotoninergic cells were found in crest cell cultures derived from vagal, thoracic/upper lumbar, and lumbosacral levels of the neuraxis. The neural crest origin of the serotonin neurons was further corroborated by the demonstration that cultures of somites, notochords, and neural tubes (three tissues adjacent to the neural crest and thus the most likely contaminants of crest cell cultures) did not contain serotonin-producing cells, and that mast cells were absent in crest cell cultures. The identification of serotoninergic neurons in quail neural crest cell cultures makes an important addition to the number of neural crest derivatives that are capable of differentiating in culture. Furthermore, it suggests that the in vitro culture system will prove a valid approach to the elucidation of the cellular and molecular mechanisms that govern neural crest cell differentiation.

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PubMed2005

Semaphorin/neuropilin signaling influences the positioning of migratory neural crest cells within the hindbrain region of the chick.

Within the hindbrain region, neural crest cell migration is organized into three streams that follow the segmentation of the neuroepithelium into distinct rhombomeric compartments. Although the streaming of neural crest cells is known to involve signals derived from the neuroepithelium, the molecular properties underlying this process are poorly understood. Here, we have mapped the expression of the signaling component of two secreted class III Semaphorins, Semaphorin (Sema) 3A and Sema 3F, at time points that correspond to neural crest cell migration within the hindbrain region of the chick. Both Semaphorins are expressed within rhombomeres at levels adjacent to crest-free mesenchyme and expression of the receptor components essential for Semaphorin activity by neural crest cells suggests a function in restricting neural crest cell migration. By using bead implantation and electroporation in ovo, we define a role for both Semaphorins in the maintenance of neural crest cell streams in proximity to the neural tube. Attenuation of Semaphorin signaling by expression of soluble Neuropilin-Fc resulted in neural crest cells invading adjacent mesenchymal territories that are normally crest-free. The loss or misguidance of specific neural crest cell populations after changes in Semaphorin signaling also affects the integration of the cranial sensory ganglia. Thus, Sema 3A and 3F, expressed and secreted by the hindbrain neuroepithelium contributes to the appropriate positioning of neural crest cells in proximity to the neural tube, a process crucial for the subsequent establishment of neuronal connectivity within the hindbrain region.

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PubMed1995

Regulative response of the cranial neural tube after neural fold ablation: spatiotemporal nature of neural crest regeneration and up-regulation of Slug.

After unilateral ablation of the avian cranial neural folds, the remaining neuroepithelial cells are able to replace the missing neural crest population (Scherson et al., 1993). Here, we characterize the cellular and molecular nature of this regulative response by defining: (1) the time and location of neural crest cell production by the neuroepithelium; (2) rostrocaudal axial differences in the regulative response; and (3) the onset of expression of Slug, a transcription factor present in premigratory and migrating neural crest cells. Using DiI and HNK-1 antibody labeling techniques, we find that neural crest regeneration occurs only after apposition of the remaining neuroepithelium with the epidermis, suggesting that the developmental mechanism underlying regeneration of the neural crest may recapitulate initial generation of the neural crest. The regulative response occurs maximally at the 3-5 somite stage, and slowly declines thereafter. Surprisingly, there are profound regional differences in the regenerative ability. Whereas a robust regulation occurs in the caudal midbrain/hindbrain, the caudal forebrain/rostral midbrain regenerates neural crest to a much lesser extent. After neural fold removal in the hindbrain, regenerated neural crest cells migrate in a segmental pattern analogous to that seen in unablated embryos; a decrease in regulative response appears to occur with increasing depth of the ablation. Up-regulation of Slug appears to be an early response after ablation, with Slug transcripts detectable proximal to the ablated region 5-8 hours after surgery and prior to emergence of neural crest cells. Both bilateral and unilateral ablations yield substantial numbers of neural crest cells, though the former recover less rapidly and have greater deficits in neural crest-derived structures than the latter. These experiments demonstrate that the regulative ability of the cranial neuroepithelium to form neural crest depends on the time, location and extent of neural fold ablation.

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PubMed1995

Segmental migration of trunk neural crest: time-lapse analysis reveals a role for PNA-binding molecules.

Trunk neural crest cells migrate through the somites in a striking segmental fashion, entering the rostral but not caudal sclerotome, via cues intrinsic to the somites. Attempts to define the molecular bases of these cues have been hampered by the lack of an accessible assay system. To examine trunk neural crest migration over time and to perturb candidate guiding molecules, we have developed a novel explant preparation. Here, we demonstrate that trunk regions of the chicken embryo, placed in explant culture, continue to develop apparently normally for 2 days. Neural crest cells, recognized by prelabeling with DiI or by poststaining with the HNK-1 antibody, migrate in the somites of the explants in their typical segmental pattern. Furthermore, this paradigm allows us to follow trunk neural crest migration in situ for the first time using low-light-level videomicroscopy. The trajectories of individual neural crest cells were often complex, with cells migrating in an episodic mode encompassing forward, backward and lateral movements. Frequently, neural crest cells migrated in close-knit groups of 2-4 cells, moving at mean rates of migration of 10-14 microns/hour. Treatment of the explants with the lectin peanut agglutinin (PNA) both slowed the rate and altered the pattern of neural crest migration. Neural crest cells entered both the rostral and caudal halves of the sclerotome with mean rates of migration ranging from 6 to 13 microns/hour. These results suggest that peanut agglutinin-binding molecules are required for the segmental patterning of trunk neural crest migration. Because this approach permits neural crest migration to be both observed and perturbed, it offers the promise of more direct assays of the factors that influence neural crest development.

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PubMed2005

Notch in the pathway: the roles of Notch signaling in neural crest development.

Here, we review recent studies that suggest that Notch signaling has two roles during neural crest development: first in establishing the neural crest domain within the ectoderm via lateral induction and subsequently in diversifying the fates of cells that arise from the neural crest via lateral inhibition. The first of these roles, specification of neural crest via lateral induction, has been explored primarily in the cranial neural folds from which the cranial neural crest arises. Evidence for such a role has thus far only been obtained from chick and frog; results from these two species differ, but share the feature that Notch signaling regulates genes that are expressed by cranial neural crest through effects on expression of Bmp family members. The second of these roles, diversification of neural crest progeny via lateral inhibition, has been identified thus far only in trunk neural crest. Evidence from several species suggests that Notch-mediated lateral inhibition functions in multiple episodes in this context, in each case inhibiting neurogenesis. In the 'standard' mode of lateral inhibition, Notch promotes proliferation and in the 'instructive' mode, it promotes specific secondary fates, including cell death or glial differentiation. We raise the possibility that a single molecular mechanism, inhibition of so-called proneural bHLH genes, underlies both modes of lateral inhibition mediated by Notch signaling.

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PubMed1998

Neural crest development: the interplay between morphogenesis and cell differentiation.

The final pattern of tissues established during embryogenesis reflects the outcome of two developmental processes: differentiation and morphogenesis. Avian neural crest cells are an excellent system in which to study this interaction. In the first phase of neural crest cell migration, neural crest cells separate from the neural epithelium via an epithelial-mesenchymal transformation. We present three models to account for this process: (1) separation by asymmetric mitosis, (2) separation by generating tractional force in order to rupture cell adhesions and (3) loss of expression or function of cell-cell adhesion molecules that keep the presumptive neural crest cells tethered to the neural epithelium. Evidence is presented that the segregation of the neural crest lineage apart from the neural epithelium is caused by the epithelial-mesenchymal transformation. Once they have detached from the neural tube, neural crest cells take two pathways in the trunk of the chick embryo: (1) the ventral path between the neural tube and somite, where neural crest cells give rise to neurons and glial cells of the peripheral nervous systems, and (2) the dorsolateral path between the ectoderm and dermamyotome of the somite, where they differentiate into pigment cells of the skin. We present data to suggest that the migration and differentiation along the ventral path is controlled primarily by environmental cues, which we refer to as the environment-directed model of neural crest morphogenesis. Conversely, only melanoblasts can migrate into the dorsolateral space, and the ability to invade that path is dependent upon their early specification as melanoblasts. We call this the phenotype-directed model for neural crest cell migration and suggest that this latter model for the positioning of neural crest derivatives in the embryo may be more common than previously suspected. These observations invite a re-examination of patterning of other crest derivates, which previously were believed to be controlled by environmental cues.

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PubMed1987

Neural crest cell migratory pathways in the trunk of the chick embryo.

Neural crest cells migrate during embryogenesis to give rise to segmented structures of the vertebrate peripheral nervous system: namely, the dorsal root ganglia and the sympathetic chain. However, neural crest cell arise from the dorsal neural tube where they are apparently unsegmented. It is generally agreed that the somites impose segmentation on migrating crest cells, but there is a disagreement about two basic questions: exactly pathways do neural crest cells use to move through or around somites, and do neural crest cells actively migrate or are they passively dispersed by the movement of somite cells? The answers to both questions are critically important to any further understanding of the mechanisms underlying the precise distribution of the neural crest cells that develop into ganglia. We have done an exhaustive study of the locations of neural crest cells in chick embryos during early stages of their movement, using antibodies to neural crest cells (HNK-1), to neural filament-associated protein in growing nerve processes (E/C8), and to the extracellular matrix molecule laminin. Our results show that Some neural crest cells invade the extracellular space between adjacent somites, but the apparent majority move into the somites themselves along the border between the dermatome/myotome (DM) and the sclerotome. Neural crest cells remain closely associated with the anterior half of the DM of developing somites as they travel, suggesting that the basal lamina of the DM may be used as a migratory substratum. Supporting this idea is our observation that the development of the DM basal lamina coincides in time and location with the onset of crest migration through the somite. The leading front of neural crest cells advance through the somite while the length of the DM pathway remains constant, suggesting active locomotion, at least in this early phase of development. Neural crest cells leave the DM at a later stage of development to associate with the dorsal aorta, where sympathetic ganglia form, and to associate with newly emerging fibers of the ventral root nerve, where they presumably give rise to neuronal supportive cells. Thus we propose that the establishment of the segmental pattern of the peripheral ganglia and nerves depends on the timely development of appropriate substrata to guide and distribute migrating neural crest cells during the early stages of embryogenesis.

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PubMed2003

Neural crest induction by paraxial mesoderm in Xenopus embryos requires FGF signals.

At the border of the neural plate, the induction of the neural crest can be achieved by interactions with the epidermis, or with the underlying mesoderm. Wnt signals are required for the inducing activity of the epidermis in chick and amphibian embryos. Here, we analyze the molecular mechanisms of neural crest induction by the mesoderm in Xenopus embryos. Using a recombination assay, we show that prospective paraxial mesoderm induces a panel of neural crest markers (Slug, FoxD3, Zic5 and Sox9), whereas the future axial mesoderm only induces a subset of these genes. This induction is blocked by a dominant negative (dn) form of FGFR1. However, neither dnFGFR4a nor inhibition of Wnt signaling prevents neural crest induction in this system. Among the FGFs, FGF8 is strongly expressed by the paraxial mesoderm. FGF8 is sufficient to induce the neural crest markers FoxD3, Sox9 and Zic5 transiently in the animal cap assay. In vivo, FGF8 injections also expand the Slug expression domain. This suggests that FGF8 can initiate neural crest formation and cooperates with other DLMZ-derived factors to maintain and complete neural crest induction. In contrast to Wnts, eFGF or bFGF, FGF8 elicits neural crest induction in the absence of mesoderm induction and without a requirement for BMP antagonists. In vivo, it is difficult to dissociate the roles of FGF and WNT factors in mesoderm induction and neural patterning. We show that, in most cases, effects on neural crest formation were parallel to altered mesoderm or neural development. However, neural and neural crest patterning can be dissociated experimentally using different dominant-negative manipulations: while Nfz8 blocks both posterior neural plate formation and neural crest formation, dnFGFR4a blocks neural patterning without blocking neural crest formation. These results suggest that different signal transduction mechanisms may be used in neural crest induction, and anteroposterior neural patterning.

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PubMed1994

Developmental potential of trunk neural crest cells in the mouse.

The availability of naturally occurring and engineered mutations in mice which affect the neural crest makes the mouse embryo an important experimental system for studying neural crest cell differentiation. Here, we determine the normal developmental potential of neural crest cells by performing in situ cell lineage analysis in the mouse by microinjecting lysinated rhodamine dextran (LRD) into individual dorsal neural tube cells in the trunk. Labeled progeny derived from single cells were found in the neural tube, dorsal root ganglia, sympathoadrenal derivatives, presumptive Schwann cells and/or pigment cells. Most embryos contained labeled cells both in the neural tube and at least one neural crest derivative, and numerous clones contributed to multiple neural crest derivatives. The time of injection influenced the derivatives populated by the labeled cells. Injections at early stages of migration yielded labeled progeny in both dorsal and ventral neural crest derivatives, whereas those performed at later stages had labeled cells only in more dorsal neural crest derivatives, such as dorsal root ganglion and presumptive pigment cells. The results suggest that in the mouse embryo: (1) there is a common precursor for neural crest and neural tube cells; (2) some neural crest cells are multipotent; and (3) the timing of emigration influences the range of possible neural crest derivatives.

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PubMed1999

Zebrafish narrowminded suggests a genetic link between formation of neural crest and primary sensory neurons.

In the developing vertebrate nervous system, both neural crest and sensory neurons form at the boundary between non-neural ectoderm and the neural plate. From an in situ hybridization based expression analysis screen, we have identified a novel zebrafish mutation, narrowminded (nrd), which reduces the number of early neural crest cells and eliminates Rohon-Beard (RB) sensory neurons. Mosaic analysis has shown that the mutation acts cell autonomously suggesting that nrd is involved in either the reception or interpretation of signals at the lateral neural plate boundary. Characterization of the mutant phenotype indicates that nrd is required for a primary wave of neural crest cell formation during which progenitors generate both RB sensory neurons and neural crest cells. Moreover, the early deficit in neural crest cells in nrd homozygotes is compensated later in development. Thus, we propose that a later wave can compensate for the loss of early neural crest cells but, interestingly, not the RB sensory neurons. We discuss the implications of these findings for the possibility that RB sensory neurons and neural crest cells share a common evolutionary origin.

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PubMed1997

Growth factor action in neural crest cell diversification.

At the onset of their migration into the embryo, many neural crest cells are pluripotent in the sense that they have the capacity to generate progeny that consist of more than one cell type. More recently, we have found that there are pluripotent neural crest cell-derived cells even at sites of terminal differentiation. These findings support the notion that cues originating from the microenvironment, at least in part, direct neural crest cell type specification. Based on the rationale that growth factors that are known to support survival of neural crest cell derivatives may have additional functions in progenitor cell development, we have examined the action of pertinent growth factors. Trophic, mitogenic, antiproliferative and differentiation promoting activities were found. Stem cell factor (SCF) is trophic for pluripotent neural crest cells. Contrary to expectation, SCF plus a neurotrophin, rather than SCF alone is trophic for committed melanogenic cells. Basic fibroblast growth factor (bFGF) is mitogenic both for pluripotent cells and committed melanogenic cells. However, the cells become dependent on another factor for survival. Whereas any neurotrophin tested can rescue bFGF-activated pluripotent neural crest cells, the factor that rescues melanogenic cells remains to be determined. Transforming growth factor beta 1 (TGF-beta 1) is a powerful antimitotic signal for all neural crest cells that overrides the bFGF/neurotrophin proliferative signal. Furthermore, SCF promotes differentiation of neural crest cells into cells of the sensory neuron lineage. Neurotrophin-3 (NT-3) specifically promotes high affinity uptake of norepinephrine by neural crest cells and is thus thought to play a critical role in the differentiation of sympathetic neuroblasts. In summary, our data indicate that neurotrophins and other pertinent growth factors affect survival, proliferation and differentiation of neural crest cells at multiple levels and in different lineages. Moreover, our findings emphasise the importance of the concerted action of combinations of growth factors, rather than of individual factors.

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PubMed1999

Regulation of Hoxa2 in cranial neural crest cells involves members of the AP-2 family.

Hoxa2 is expressed in cranial neural crest cells that migrate into the second branchial arch and is essential for proper patterning of neural-crest-derived structures in this region. We have used transgenic analysis to begin to address the regulatory mechanisms which underlie neural-crest-specific expression of Hoxa2. By performing a deletion analysis on an enhancer from the Hoxa2 gene that is capable of mediating expression in neural crest cells in a manner similar to the endogenous gene, we demonstrated that multiple cis-acting elements are required for neural-crest-specific activity. One of these elements consists of a sequence that binds to the three transcription factor AP-2 family members. Mutation or deletion of this site in the Hoxa2 enhancer abrogates reporter expression in cranial neural crest cells but not in the hindbrain. In both cell culture co-transfection assays and transgenic embryos AP-2 family members are able to trans-activate reporter expression, showing that this enhancer functions as an AP-2-responsive element in vivo. Reporter expression is not abolished in an AP-2(alpha) null mutant embryos, suggesting redundancy with other AP-2 family members for activation of the Hoxa2 enhancer. Other cis-elements identified in this study critical for neural-crest-specific expression include an element that influences levels of expression and a conserved sequence, which when multimerized directs expression in a broad subset of neural crest cells. These elements work together to co-ordinate and restrict neural crest expression to the second branchial arch and more posterior regions. Our findings have identified the cis-components that allow Hoxa2 to be regulated independently in rhombomeres and cranial neural crest cells.

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PubMedDate not supplied

Latent homologues for the neural crest as an evolutionary novelty.

The neural crest is a craniate synapomorphy and a bona fide evolutionary novelty. Recently, researchers considering intriguingly similar patterns of gene expression, cell behaviors, and embryogenetic processes in noncraniate deuterostomes have suggested that cephalochordates, urochordates, and echinoderms or their ancestors might have possessed cells that were precursors to the neural crest or its constituent cells. To emphasize the caution with which similarities at genetic, cellular, or embryological levels should be interpreted as substantiations for cell, germ layer, or tissue homologies, we present and evaluate additional tantalizing evidence that could be considered as documenting neural crest precursors in precraniates. Furthermore, we propose an evolutionary context--latent homologue--within which these data should be interpreted.

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PubMed2003

Cardiac neural crest contributes to cardiomyogenesis in zebrafish.

In birds and mammals, cardiac neural crest is essential for heart development and contributes to conotruncal cushion formation and outflow tract septation. The zebrafish prototypical heart lacks outflow tract septation, raising the question of whether cardiac neural crest exists in zebrafish. Here, results from three distinct lineage-labeling approaches identify zebrafish cardiac neural crest cells and indicate that these cells have the ability to generate MF20-positive muscle cells in the myocardium of the major chambers during development. Fate-mapping demonstrates that cardiac neural crest cells originate both from neural tube regions analogous to those found in birds, as well as from a novel region rostral to the otic vesicle. In contrast to other vertebrates, cardiac neural crest invades the myocardium in all segments of the heart, including outflow tract, atrium, atrioventricular junction, and ventricle in zebrafish. Three distinct groups of premigratory neural crest along the rostrocaudal axis have different propensities to contribute to different segments in the heart and are correspondingly marked by unique combinations of gene expression patterns. Zebrafish will serve as a model for understanding interactions between cardiac neural crest and cardiovascular development.

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PubMed1982

The neural crest: its relations with APUD and paraneuron concepts.

The neural crest cells give rise to a large variety of derivatives including neural, mesenchymal, APUD and/or paraneuron cell types. A better knowledge of these derivatives was partly achieved through studies using Le Douarin's quail/chick marker system. We review here evidences which were thus provided for a neural crest origin of calcitonin containing cells, carotid body, aortic paraganglia, adrenomedulla, and against a neurectodermal origin of enterogastric and respiratory tract endocrine cells. The role of neural crest cells in Pearse's APUD system is discussed. The results implicate that an explanation for the common properties of these cell types and their pathological and biochemical significance should not be looked for in a common embryological origin but at another level. The place of neural crest and, more generally, neurectoderm derivatives in the paraneuron concept of Fujita is examined. The relevance of the epithelial origin of these cell types to their "receptosecretory" function is stressed. Considering neural crest itself as a unique system is still questioned and discussed here. Its ubiquity and penetration of other systems is pointed out as a widespread phenomenon which is not restricted to APUD and paraneuron systems.

APUD Cells↗
PubMed1989

Developmental potential of avian trunk neural crest cells in situ.

To analyze the developmental potential of individual neural crest cells or their precursors, we have microinjected a vital dye, lysinated rhodamine dextran (LRD), into single cells in the dorsal neural tube. The phenotypes of the descendants that inherited the LRD from the injected cells were evaluated based upon their position, morphology, and neurofilament expression. Individual neural crest cells labeled before or as they emigrated from the neural tube gave rise to both sensory and sympathetic neurons as well as nonneuronal cells, some of which had the morphological characteristics of Schwann cells or pigment cells. In numerous cases, the descendants of a single cell included both neural crest- and neural tube-derived neurons, suggesting that some cells of the peripheral and central nervous systems share a common lineage. Our data demonstrate definitively that both emigrating and premigratory trunk neural crest cells can be multipotent, giving rise not only to cells in multiple neural crest derivatives, but also to both neuronal and nonneuronal elements within a given derivative.

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PubMed2004

Graded potential of neural crest to form cornea, sensory neurons and cartilage along the rostrocaudal axis.

Neural crest cells arising from different rostrocaudal axial levels form different sets of derivatives as diverse as ganglia, cartilage and cornea. These variations may be due to intrinsic properties of the cell populations, different environmental factors encountered during migration or some combination thereof. We test the relative roles of intrinsic versus extrinsic factors by challenging the developmental potential of cardiac and trunk neural crest cells via transplantation into an ectopic midbrain environment. We then assess long-term survival and differentiation into diverse derivatives, including cornea, trigeminal ganglion and branchial arch cartilage. Despite their ability to migrate to the periocular region, neither cardiac nor trunk neural crest contribute appropriately to the cornea, with cardiac crest cells often forming ectopic masses on the corneal surface. Similarly, the potential of trunk and cardiac neural crest to form somatosensory neurons in the trigeminal ganglion was significantly reduced compared with control midbrain grafts. Cardiac neural crest exhibited a reduced capacity to form cartilage, contributing only nominally to Meckle's cartilage, whereas trunk neural crest formed no cartilage after transplantation, even when grafted directly into the first branchial arch. These results suggest that neural crest cells along the rostrocaudal axis display a graded loss in developmental potential to form somatosensory neurons and cartilage even after transplantation to a permissive environment. Hox gene expression was transiently maintained in the cardiac neural tube and neural crest at 12 hours post-transplantation to the midbrain, but was subsequently downregulated. This suggests that long-term differences in Hox gene expression cannot account for rostrocaudal differences in developmental potential of neural crest populations in this case.

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