The stem cells of the neural crest - Taylor & Francis Online

[Cell Cycle 7:8, 1013-1019; 15 April 2008]; ©2008 Landes Bioscience

Review

The stem cells of the neural crest Nicole M. Le Douarin,* Giordano W. Calloni and Elisabeth Dupin CNRS UPR2197 Laboratoire Développement; Evolution et Plasticité du Système Nerveux; Institut de Neurobiologie Alfred Fessard; Gif-sur-Yvette, France

Abbreviations: NC, neural crest; NCC, neural crest cells; PNS, peripheral nervous system; Shh, sonic hedgehog; d6, day 6 of culture; HSC, hemopoietic stem cell; NCSC, neural crest stem cell

OT D

IST RIB

been reviewed by Sven Horstadius in 1950 in a well-acknowledged monograph.1 However, the paramount role of this structure in the ontogeny of the higher forms of vertebrates had to await the advent of appropriate cell marking techniques to be disclosed. These investigations started in the 1960ies with the use of tritiated thymidine, which transiently labels dividing cells (reviewed in ref. 2). More stable and easier to use was the quail-chick chimera system devised in 1969 by one of us.3,4 The research based on this cell marking technique and carried out over the last 38 years on the avian embryo has deciphered the contribution of these wandering embryonic cells to a number of anatomical structures and tissues of the avian embryo (Table 1). The NC cells (NCC) appear as an impressively invasive type of cells since there is no tissue and organ in the body that these cells do not colonize (reviewed in refs. 5 and 6). Recently developed, genetically engineered cell labeling techniques that can be applied to the mouse embryo (reviewed in refs. 7–9) have extended these investigations to mammals and generally confirmed that what is true, in this respect, for birds is also true for mammals. The NC is at the origin of the peripheral nervous system (PNS), the melanocytes and some endocrine cells (Table 1). In all vertebrates a large part of the skull and the entire facial skeleton are derived from the cephalic NC (extending from the mid-diencephalon down to the level of somite 4–5 boundary) (reviewed in refs. 6–10). In extant teleosts, the NC also provides the dorsal fin with its bony components, meaning that, at the trunk level, it is endowed with the capacity to yield mesenchymal cells. It is considered very likely that the superficial skeleton of the ostracoderms had a NC origin since it contains dentin, which is a marker of NC-derived superficial bony tissues. In higher vertebrates, the head skeleton and the teeth are the only remnants of this ancestral state (reviewed in ref. 11). No type of mesenchymal cells has been found to arise from the trunk NC in the avian embryo in vivo by using the quail-chick chimera system.5 However, a contribution of the trunk NC to the endoneurial fibroblasts of the sciatic nerve has been shown in the mouse.12 Moreover, genetic fate mapping using the neuroepithelial marker Sox1 and the NC marker Po has recently suggested that a first, transitory wave of mesenchymal stem cells in the early mouse embryo derive from trunk NCC.13 In the course of embryogenesis, the NC has thus a unique status since, while belonging to the ectodermal germ layer and evolving as part of the neural primordium, it yields cell types that are

ND

ES

BIO

SC

IEN CE

.D

ON

In the vertebrate embryo, the neurectodermal neural crest cells (NCC) have remarkably broad potencies, giving rise, after a migratory phase, to neurons and glial cells in the peripheral nervous system, and to skin melanocytes, being all designated here as “neural” derivatives. NC-derived cells also include non-neural, “mesenchymal” cell types like chondrocytes and bone cells, myofibroblasts and adipocytes, which largely contribute to the head structures in amniotes. Similar to the blood cell system, the NC is therefore a valuable model to investigate the mechanisms of cell lineage diversification in vertebrates. Whether NCC are endowed with multiple differentiation potentials or if, conversely, they are a mosaic of different committed cells is an important ongoing issue to understand the ontogeny of NC derivatives in normal development and pathological conditions. Here we focus on recent findings that established the presence in the early migratory NC of the avian embryo, of a multipotent progenitor endowed with both mesenchymal and neural differentiation capacities. This “mesenchymal-neural” clonogenic cell lies upstream of all the other NC progenitors known so far and shows increased frequency when single cell cultures are treated with the Sonic Hedgehog signaling molecule. These findings are discussed in the context of the broad potentials of NC stem cells recently evidenced in certain adult mammalian tissues.

UT E

.

Key words: stem cell, mesenchymal, neural, quail embryo, clonal culture, multipotentiality, chondrocyte, in vitro culture

LA

Introduction

©

20

08

The neural crest (NC) is a discrete embryonic structure of the vertebrates, discovered by Wilhem His in 1868 in the chick embryo as a strand of cells lying on the dorsal aspect of the closing neural tube. The NC is thus a part of the neural primordium, which rapidly spreads all over the embryo through the extensive migration of its component cells. It was the subject of active investigations in lower vertebrates (namely fish and amphibians) during the first half of the twentieth century. Most of the work carried out during this period has *Correspondence to: Nicole M. Le Douarin; CNRS UPR2197 Laboratoire DEPSN; Institut de Neurobiologie Alfred Fessard; 91198 Gif-sur-Yvette, France; Tel: 33.144414358; Fax: 33.144414586; Email: [email protected] Submitted: 01/24/08; Accepted: 01/24/08 Previously published online as a Cell Cycle E-publication: http://www.landesbioscience.com/journals/cc/article/5641 www.landesbioscience.com

Cell Cycle

1013

Neural crest stem cells

Head & Trunk NC

“Neural” derivatives

Neurons of PNS ganglia (sensory, autonomic and enteric)

Glial cells (PNS ganglia and Schwann cells)

Melanocytes (skin and inner ear)

Endocrine cells (adrenomedullary cells and thyroid C cells)

Head NC

“Mesenchymal” derivatives

Chondrocytes

Osteocytes

Myofibroblasts/Smooth muscle cells Adipocytes

UT E

.

Connective tissue cells Meninges (forebrain)

IST RIB

The Heterogeneity of the NC Precursor Cells at Migratory Stages

OT D

A Parallel Between Hemopoiesis and NC Development

Table 1 Cell phenotypes derived from the NC in amniotes

In order to answer the question raised as to whether a common precursor for “neural” and “mesenchymal” derivatives of the NC (further designated here as “mesenchymal-neural” progenitor) exists in the avian embryo, we have selectively explored the differentiation potentialities of the cephalic NCC of the developing quail. A culture medium was devised using a feeder-layer of growth-inhibited 3T3 mouse cells.15 The characteristic of this clonogenic culture condition is that it provides NCC with the possibility to express virtually all their developmental capacities, a situation that is strikingly different from that prevailing in vivo: while NCC widely invade the developing embryo, they differentiate into a limited set of cell types in each site where they settle, such as neurons and glia in the PNS ganglia or pigment cells in the skin. At early migration stages, the NCC population turned out to be heterogeneous as far as the differentiation capacity of its component cells is concerned.15-18,34,35 Some clones contained only neurons (about 1% of the clones) or only glia (more than 30%) and were thus derived from monopotent, fully committed progenitors. The majority of the clones however were composed of two different cell phenotypes (i.e., glia-neurons, and, less frequently, glia-melanocytes and glia-myofibroblasts). Colonies containing three or four different NC derivatives represented about 14% of the clonogenic cells. Noticeably, the capacity to generate representatives of both the “neural” (glia, neurons and melanocytes) together with the chondrocytic cell type, which in these experiments was the representative of the mesenchymal potentialities of differentiation, was evidenced in only a small number (2.5%) of clonogenic NCC15-18 (Table 2). The existence of a clonogenic cell able to yield all the phenotypes normally derived from the NC in vivo, i.e., a cell yielding glia (G), neurons (N), melanocytes (M), myofibroblasts (F) and chondrocytes (C): GNMFC, could not be proven until we recently showed that the outcome of clonal and mass cultures of cephalic NCC harvested after they have migrated out of the neural tube depends upon the time during which the neural tube and the migratory NCC have

ON

typically derivatives of the mesodermal germ layer such as connective and adipose tissues, cartilage and bone. It has for this reason, been considered by some authors in the past as a fourth germ layer, segregating late from the ectoblast during the neurulation process. This notion has been resuscitated by Weston et al.,14 who argued that the mesenchymal and neural-melanocytic cell lineages exiting from the neural fold might be different in origin, the former being derived from the superficial ectoderm and the latter only being part of the neural primordium. This hypothetical view based upon differential expression of E-cadherin and Platelet-derived growth factor receptor α, however still lacks experimental support. The problem of the segregation of cell lineages in the NC derivatives has for long been a subject of interest for our laboratory.15-19 Here we discuss insights provided by in vitro experiments aimed at deciphering the developmental capacities of individual NCC and namely, their potential to giving rise to both “neural derivatives” (including neurons, glia, endocrine cells and melanocytes) and “mesenchymal derivatives” (such as myofibroblasts, bone and cartilage, and adipose tissue cells (see Table 1). This issue is interesting in the present context where mesenchymal progenitors and stem cells have been found in various adult tissues (reviewed in refs. 20 and 21). These cells, isolated using a variety of culture techniques, exhibit multiple differentiation capacities (including neural properties), which are extensively discussed and the subject of diverse interpretations.22

LA

ND

ES

BIO

SC

IEN CE

.D

During the course of our investigations an inspiring model for our research on the developmental potentialities of NCC was the methodological and conceptual analysis used from the 1950ies onward to decipher the origin of blood cell diversity. The derivation of multiple cell types from an originally small number of undifferentiated cells, the mobility of these cells and their widespread distribution all over the body, are common features of the development of hemopoietic and NC derivatives. This is why the NCC development has been designated as “neuropoiesis”.23 It has been clearly established that all the cell types present in the blood are derived from a common precursor, the hemopoietic stem cell (HSC) endowed with self-renewal properties.24-27 It was therefore tempting to ask whether such multipotent stem cells exist also in the NC. This putative NC stem cell should be able to yield both “mesenchymal” and “neural” derivatives and, for deserving the designation of “stem” cell, it should also be able to self-renew.

08

In vitro Clonal Analysis of NCC

©

20

Several laboratories have been involved in such an endeavor. The possibility of culturing single NCC, was first demonstrated by Cohen and Konigsberg28 in the quail species. In our laboratory, isolation of single cells was carried out either directly from migratory NCC removed from quail embryos at the cephalic level, or from the NCC outgrowth produced by trunk and cephalic neural tubes cultured before the onset of the migration. Within the first 24 hours in vitro, the NCC that had migrated from the explants on the substrate of the culture dish, were harvested. In both cases single cells were isolated and seeded in culture plates by micromanipulation. Clonogenic cells developed colonies in which the different phenotypes that differentiated were recorded.15-18 Similar investigations were also carried out in other laboratories using quail (reviewed in refs. 29–31) or mammalian species NCC (reviewed in refs. 32 and 33). 1014

Cell Cycle

2008; Vol. 7 Issue 8


GNMC

0.15%

C (mesenchymal)

(Ref. 15–17)

GNC

0.15%

GC

2.5%

Total C+

2.8%

G, N, M (neural)

N = 199

GNMF

6%

F, C (mesenchymal)

(Ref. 18)

GMFC

1%

GMC

0.5%

GNF

1%

GMF

8.5%

GF

Total C+

Total F+

4% 1.5% 20.5%

ON

Multipotent and bipotent progenitors were identified by in vitro clonal analysis of cephalic NCC, which gave rise to both “neural” cell types, i.e., glia (G), neurons (N) and melanocytes (M) and to mesenchymal cells. In a first series of experiments, cartilage (C) was the only representative phenotype of mesenchymal NC derivatives analysed in the clones (N = 643) (data from15-17); in a second series of clonal cultures (N = 199), myofibroblasts (F) were also recorded in addition to chondrocytes (18 and ED and NMLD, unpublished data). The frequency (percent of clonogenic cells) of cartilage-producing progenitors (Total C+) was very low compared with the ratio of those able to generate myofibroblasts (Total F+).

In a recent work,19 we have raised the question of the nature of the putative factors involved in the growth and differentiation of the mesenchymal precursors of the cephalic NC, which are responsible for the development of the facial skeleton.50,51 Several lines of evidence based on in vivo experiments in the mouse52,53 and chick5457 embryos pointed to the requirement of Sonic Hedgehog (Shh) for facial morphogenesis by cephalic NCC. This led us to investigate the possible effect of this morphogen on the differentiation of cartilage in mass and clonal cephalic NCC cultures19 (Fig. 1). It was found that addition of Shh to the conventional culture medium at the concentration of 100 ng/ml influences positively the differentiation of cartilage nodules in mass cultures (400 cells per well). However, this action depends on the developmental stage at which it is added to the migratory NCC. As mentioned above, the strongest response to Shh was obtained from cells that were left in the presence of the mesencephalic neural primordium from which they migrate, no longer than 15 hours. Moreover, the efficient time window of Shh exposure was found to be during the first two days of culture of the pure population of migratory NCC. The response to Shh was not an increase of the total number of cephalic NCC, which, at day 6 of culture (d6) was the same in presence and in absence of Shh treatment. The effect of Shh consisted in an increase of the number of cultures containing cartilage nodules as well as the number of such nodules per well. The presence of chondrocytes was evidenced both by their morphology and the expression of the chondrocyte-specific transcription factor Sox9,58-60 the presence of chondroitin sulfate and Alcian blue staining.19 Further insight into the action of Shh on the differentiation of the mesencephalic NCC was obtained when the clonogenicity and differentiation capacities of these cells were explored. Shh increased the number of cells able to yield the complete repertoire of cephalic NCC derivatives: glia, neurons, melanocytes, myofibroblasts and chondrocytes (GNMFC) without increasing NCC clonogenicity. In the culture conditions defined above (Fig. 1), we have thus observed for the first time the differentiation of highly multipotent clonogenic cells, i.e., the “mesenchymal-neural” or GNMFC progenitors. The rate of GNMFC raise from 6.5% of d10-clones in the absence of Shh (n = 126) up to 18.5% (n = 150) following exposure to Shh for the first 2 days of culture. Moreover, in Shh-treated cultures, the multipotency of the intermediate progenitors increased significantly; two of them endowed with chondrogenic potential (i.e., GNFC and GFC) had not been identified before. Notably, the increase of the proportion of “mesenchymal-neural” progenitors coincided with a decrease in the rate of the “only-neural” ones while the total number of clones remained similar in Shh-treated and untreated cultures (Fig. 2). Taken together, the clones containing both cartilage and “neural” cell types accounted for 13% and 39% of untreated and Shh-treated cultures, respectively, thus providing further support for a crucial role of Shh on multipotent chondrogenic NCC. As a whole, the most significant information that came out of these experiments19 was that Shh expands the proportion of the “mesenchymal-neural” progenitors at the expense of the “only-neural” ones.

.

N = 643

UT E

G, N, M (neural)

Effect of Sonic Hedgehog on the Development of “Mesenchymal-Neural” Progenitors

IST RIB

Phenotypes analyzed N. of clones Progenitors Type Frequency

the vasoactive peptide endothelin-3 in the development of the melanocytic and glial lineages both in culture and in vivo.18,35,46-49

OT D

Table 2 Progenitors of both “mesenchymal” and “neural” derivatives identified by clonal analysis of cephalic NCC

©

20

08

LA

ND

ES

BIO

SC

IEN CE

.D

been juxtaposed in the culture dish. When the co-culture lasted 36 or 48 hours, no cartilage nodules were detected in mass cultures at d6 (unpublished data). In contrast, when the duration of the co-culture did not exceed 15 hours, mass cultures of mesencephalic NCC exhibited cartilage nodules in a significant proportion (15%) of the cultures and GNMFC clonogenic cells were recorded in 6.5% of the clones examined (n = 126).19 It seems therefore that the presence of the neural tube in the culture medium does not favor the development of these multipotent “mesenchymal-neural” precursors that are present (at least for a while) in the early migrating NCC population. Similar observations had been reported concerning other cell phenotypes such as the influence of the neural tube on the differentiation of pigment cells and adrenergic cells in trunk NCC cultures.36,37 The nature of the factors that influence these fate decisions of NCC is still unknown. Other signaling molecules however, able to exert a selection (whether positive or negative) on the developmental capacities of NCC in the site where they settle at the term of their migration, have been identified (reviewed in refs. 38 and 39).

Cytokine-like Factors in Neuropoiesis This selection is exerted by signaling molecules generally designated as cytokines in the hemopoietic system, where such factors are also critical for the differentiation of the various types of blood cells (reviewed in ref. 40). Brain-derived neurotrophic factor41 and Wnt1 protein42 were thus shown to favor the differentiation of NC-derived sensory neurons while bone morphogenetic protein-2 promoted that of autonomic adrenergic neurons.43 Glial cell differentiation of NCC was shown to depend upon a factor of neuronal origin, neuregulin-1.44,45 In our laboratory, we could demonstrate the strong implication of www.landesbioscience.com

Cell Cycle

1015

IST RIB

UT E

.


.D

ON

OT D

Figure 1. Schematic methodology of isolation and culture of quail NCC. Neural tubes (with pre-migratory NC) were taken at the cephalic and trunk levels from quail embryos at 6 somite-stage (A) and 18–25 somite-stage (B), respectively. The isolated neural tubes (NT) were maintained in primary culture. After 15 hr (cephalic) or 24 hr (trunk), the NCC that had migrated around the explanted neural tubes were harvested for secondary cultures. Mass cultures contained 400 cells per well for cephalic NCC and 800 cells per well for trunk NCC. Clonal cultures were performed by seeding NCC individually in culture wells with a micropipette under microscopic control. NCC were grown on previously established feeder layer of growth-arrested 3T3 fibroblasts. At d6 to d10, cell phenotypes produced by cephalic and trunk NCC were identified by using lineage-specific markers.19

©

20

08

LA

ND

ES

BIO

SC

IEN CE

Figure 2. Model of lineage segregation and Shh action in cephalic NCC. Progenitors identified by in vitro clonal analysis of cephalic NCC are ordered according to their number of developmental potentialities (data from17-19). Neurons (N), glia (G), melanocytes (M) and mesenchymal derivatives, i.e., myofibroblasts (F) and cartilage (C) arise from diverse “intermediate” multipotent and bipotent precursors, some of which are capable to self-renew in vitro (curved arrows).18 This hierarchical model suggests that committed cells are generated through progressive restrictions in the potentialities of a highly multipotent progenitor (GNMFC) that was recently identified in early migratory cells.19 Whether this progenitor is endowed with self-renewal capacity remains to be tested. Newly identified progenitors that yield chondrocytes19 are indicated by thicken circles. The scheme emphasizes three categories of precursors, those which yield only “neural” derivatives (G, N and/or M) (in yellow), those which yield only mesenchymal cells (C and/or F) (in blue) and the “mesenchymal-neural” ones, displaying at least one representative of both neural and mesenchymal potentials (yellow-blue). The table indicates the proportion of these three categories of progenitors in control and Shh-supplemented medium; treatment with Shh increases the percentage of clones exhibiting “mesenchymal-neural” potentialities while decreasing the frequency of the “only-neural” colonies.

“Mesenchymal-Neural” Progenitors in the Avian Trunk NC as Remnants of an Ancestral State A potential to generate skeletal derivatives had been previously discovered in the avian trunk NC following long-term culture and transplantation into the branchial arch of chick embryos.61,62 Since our recent work significantly improved the rate of chondrogenic differentiation of cranial NCC, we have challenged trunk NCC development in vitro with recombinant Shh. Although occurring at a much lower frequency than in mesencephalic NCC cultures, chondrogenesis in mass cultures of trunk NCC was promoted by treatment with Shh, which increased the estimated rate of 1016

chondrogenic cells from 0.04% to 0.25% of plated cells. In clonal assay, we identified a single chondrogenic progenitor out of 225 truncal NCC treated with Shh. This progenitor yielded glial cells, myofibroblasts and chondrocytes (GFC), therefore revealing that trunk NCC include rare oligopotent cells endowed with both mesenchymal and neural potentials.19 Together with the recent demonstration that trunk NCC in primary culture can

Cell Cycle



SC

OT D

IEN CE

.D

ON

Figure 3. Fate and potential of NCC according to their rostro-caudal origin. The in vivo fates (left) and the differentiation potentials as determined by in vitro cultures (right) of avian NCC are shown with respect to “neural” (yellow) and mesenchymal, i.e., chondrocytic (blue) phenotypes. The latter is restricted to the cephalic NC in vivo whereas neural derivatives are distributed equally along the rostro-caudal axis. Mesenchymal chondrogenic differentiation can be elicited in trunk NCC under in vitro conditions. The chondrogenic rate of trunk NCC however is very low relative to that observed in cultures of cephalic NCC; cephalic NCC also show an anterior to posterior graded decrease of chondrogenesis from the mesencephalon (Mes) to the posterior rhombencephalon (rhombomere 3, R3 to R8) (reviewed in ref. 19 and unpublished data). S, somite.

IST RIB

UT E

.

expressed, meaning that they depend significantly upon the environmental cues to which NCC are subjected. The clonal analyses that have revealed the developmental capacities of single NCC support the contention that the “mesenchymalneural” (GNMFC) cell represents the multipotent “stem cell” of the NC (or true NC stem cell: NCSC) equivalent to the HSC that is capable of reconstituting the complete set of blood cells in lethally irradiated mice. However, in contrast to the HSC, the self-renewal capacity of the NCSC has not yet been demonstrated. Notable is the fact that such a property has been established for intermediate bipotent and tripotent progenitors of the NCC lineages. This is the case of the GM, GF and GMF progenitors in the quail18 (Fig. 2) and GNF progenitors in mammals32,64 which undoubtedly deserve to be considered as stem cells. The fact that we have devised culture conditions that notably increase the frequency of the “GNMFC” makes it likely that the proof of their self-renewal capacity will soon be obtained. In addition to the early migratory NC, several NC derivatives at post-migratory stages still contain undifferentiated cells able to generate neurons, glia and/or myofibroblasts, which persist at late embryonic stages and even in certain adult tissues of birds and mammals, like PNS ganglia,65-71 gut,72,73 skin,74,75 heart,76 cornea77 and carotid body.78 The NC stem cell populations recently identified in the murine and human skin display neural and mesenchymal (including chondrogenic) differentiation properties and can be expanded as spheres in vitro.74,75,79-81 In the mouse, genetic fate mapping led to ascertain the NC origin of these cells both at trunk and cephalic axial levels. Multipotent cells are thus located in several structures of the whisker follicle, which are derived from the cephalic NC and, in the back skin, the trunk NC-derived multipotent cells share early markers of glial cell and melanocytic lineages.81 One can thus hypothesize that such adult stem cells are derived from embryonic NCC endowed with the full differentiation capacities of the NC early progenitors, such as the “mesenchymal-neural” ones that we have evidenced in the embryo.

©

20

08

LA

ND

ES

BIO

differentiate into adipocytes,63 these findings therefore show that NCC potentialities, whether mesenchymal or neural, are widespread but differentially distributed along the axial level in amniotes (Fig. 3). It seems likely that the NCC have been the first skeletogenic cells to appear in the vertebrate phyllum. NCC have been assumed to be at the origin of superficial dermal calcified tissues with dentin-like structures, which were the most primitive skeletal structures of the early vertebrates.11 The only remnants of this more extended armor of extinct vertebrates are the dorsal fin in teleosts and the craniofacial skeleton in both lower and higher vertebrates. We therefore propose that the “mesenchymal-neural” progenitors identified in the avian NC are more primitive than the “only-neural” ones. During evolution, regression of the superficial bony structures substituted for by the internal skeleton, resulted in the strong reduction of mesenchymal potencies in the NCC, which vanished but did not completely disappear in the trunk region of amniotes. As highlighted by our recent work,19 the potential of giving rise to mesenchymal derivatives has not been completely lost by some of these “neural” progenitors and can be revealed in vitro by the action of Shh signaling.

Concluding Remarks The in vitro experiments discussed above have revealed that the developmental capabilities of single NCC are remarkably broad. These capabilities, however, need appropriate conditions to be www.landesbioscience.com

Acknowledgements

The authors acknowledge the support of the Centre National de la Recherche Scientifique, Collège de France, Fondation Bettencourt Schueller and Association pour la Recherche contre le Cancer (grant N. 3929). GWC was recipient of a fellowship from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), Brazil. References 1. Hörstadius S. The neural crest. Its properties and derivatives in the light of experimental research. London: Oxford University Press, 1950. 2. Weston JA. The migration and differentiation of neural crest cells. Adv Morphog 1970; 8:41-114. 3. Le Douarin N, Barq G. [Use of Japanese quail cells as “biological markers” in experimental embryology]. C R Acad Sci Hebd Seances Acad Sci D 1969; 269:1543-6. 4. Le Douarin N. A biological cell labeling technique and its use in expermental embryology. Dev Biol 1973; 30:217-22. 5. Le Douarin N. The neural crest. Cambridge: Cambridge University Press, 1982. 6. Le Douarin N, Kalcheim C. The neural crest. Cambridge ; New York: Cambridge University Press, 1999. 7. Jiang X, Rowitch DH, Soriano P, McMahon AP, Sucov HM. Fate of the mammalian cardiac neural crest. Development 2000; 127:1607-16. 8. Chai Y, Jiang X, Ito Y, Bringas P, Jr., Han J, Rowitch DH, Soriano P, McMahon AP, Sucov HM. Fate of the mammalian cranial neural crest during tooth and mandibular morphogenesis. Development 2000; 127:1671-9. 9. Matsuoka T, Ahlberg PE, Kessaris N, Iannarelli P, Dennehy U, Richardson WD, McMahon AP, Koentges G. Neural crest origins of the neck and shoulder. Nature 2005; 436:347-55.

Cell Cycle

1017


OT D

IST RIB

UT E

.

43. Shah NM, Groves AK, Anderson DJ. Alternative neural crest cell fates are instructively promoted by TGFbeta superfamily members. Cell 1996; 85:331-43. 44. Shah NM, Marchionni MA, Isaacs I, Stroobant P, Anderson DJ. Glial growth factor restricts mammalian neural crest stem cells to a glial fate. Cell 1994; 77:349-60. 45. Leimeroth R, Lobsiger C, Lussi A, Taylor V, Suter U, Sommer L. Membrane-bound neuregulin1 type III actively promotes Schwann cell differentiation of multipotent Progenitor cells. Dev Biol 2002; 246:245-58. 46. Lahav R, Ziller C, Dupin E, Le Douarin NM. Endothelin 3 promotes neural crest cell proliferation and mediates a vast increase in melanocyte number in culture. Proc Natl Acad Sci USA 1996; 93:3892-7. 47. Nataf V, Lecoin L, Eichmann A, Le Douarin NM. Endothelin-B receptor is expressed by neural crest cells in the avian embryo. Proc Natl Acad Sci USA 1996; 93:9645-50. 48. Lecoin L, Sakurai T, Ngo MT, Abe Y, Yanagisawa M, Le Douarin NM. Cloning and characterization of a novel endothelin receptor subtype in the avian class. Proc Natl Acad Sci USA 1998; 95:3024-9. 49. Nataf V, Grapin-Botton A, Champeval D, Amemiya A, Yanagisawa M, Le Douarin NM. The expression patterns of endothelin-A receptor and endothelin 1 in the avian embryo. Mech Dev 1998; 75:145-9. 50. Couly GF, Coltey PM, Le Douarin NM. The triple origin of skull in higher vertebrates: a study in quail-chick chimeras. Development 1993; 117:409-29. 51. Couly G, Creuzet S, Bennaceur S, Vincent C, Le Douarin NM. Interactions between Hox-negative cephalic neural crest cells and the foregut endoderm in patterning the facial skeleton in the vertebrate head. Development 2002; 129:1061-73. 52. Chiang C, Litingtung Y, Lee E, Young KE, Corden JL, Westphal H, Beachy PA. Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function. Nature 1996; 383:407-13. 53. Jeong J, Mao J, Tenzen T, Kottmann AH, McMahon AP. Hedgehog signaling in the neural crest cells regulates the patterning and growth of facial primordia. Genes Dev 2004; 18:937-51. 54. Helms JA, Kim CH, Hu D, Minkoff R, Thaller C, Eichele G. Sonic hedgehog participates in craniofacial morphogenesis and is downregulated by teratogenic doses of retinoic acid. Dev Biol 1997; 187:25-35. 55. Ahlgren SC, Bronner Fraser M. Inhibition of sonic hedgehog signaling in vivo results in craniofacial neural crest cell death. Curr Biol 1999; 9:1304-14. 56. Cordero D, Marcucio R, Hu D, Gaffield W, Tapadia M, Helms JA. Temporal perturbations in sonic hedgehog signaling elicit the spectrum of holoprosencephaly phenotypes. J Clin Invest 2004; 114:485-94. 57. Brito JM, Teillet MA, Le Douarin NM. An early role for sonic hedgehog from foregut endoderm in jaw development: ensuring neural crest cell survival. Proc Natl Acad Sci USA 2006; 103:11607-12. 58. Ng LJ, Wheatley S, Muscat GE, Conway-Campbell J, Bowles J, Wright E, Bell DM, Tam PP, Cheah KS, Koopman P. SOX9 binds DNA, activates transcription, and coexpresses with type II collagen during chondrogenesis in the mouse. Dev Biol 1997; 183:108-21. 59. Zhao Q, Eberspaecher H, Lefebvre V, De Crombrugghe B. Parallel expression of Sox9 and Col2a1 in cells undergoing chondrogenesis. Dev Dyn 1997; 209:377-86. 60. Mori Akiyama Y, Akiyama H, Rowitch DH, de Crombrugghe B. Sox9 is required for determination of the chondrogenic cell lineage in the cranial neural crest. Proc Natl Acad Sci USA 2003; 100:9360-5. 61. McGonnell IM, Graham A. Trunk neural crest has skeletogenic potential. Curr Biol 2002; 12:767-71. 62. Abzhanov A, Tzahor E, Lassar AB, Tabin CJ. Dissimilar regulation of cell differentiation in mesencephalic (cranial) and sacral (trunk) neural crest cells in vitro. Development 2003; 130:4567-79. 63. Billon N, Iannarelli P, Monteiro MC, Glavieux-Pardanaud C, Richardson WD, Kessaris N, Dani C, Dupin E. The generation of adipocytes by the neural crest. Development 2007; 134:2283-92. 64. Morrison SJ, White PM, Zock C, Anderson DJ. Prospective identification, isolation by flow cytometry, and in vivo self-renewal of multipotent mammalian neural crest stem cells. Cell 1999; 96:737-49. 65. Ayer-Le Lievre CS, Le Douarin NM. The early development of cranial sensory ganglia and the potentialities of their component cells studied in quail-chick chimeras. Dev Biol 1982; 94:291-310. 66. Schweizer G, Ayer-Le Lievre C, Le Douarin NM. Restrictions of developmental capacities in the dorsal root ganglia during the course of development. Cell Differ 1983; 13:191-200. 67. Dupin E. Cell division in the ciliary ganglion of quail embryos in situ and after backtransplantation into the neural crest migration pathways of chick embryos. Dev Biol 1984; 105:288-99. 68. Duff RS, Langtimm CJ, Richardson MK, Sieber Blum M. In vitro clonal analysis of progenitor cell patterns in dorsal root and sympathetic ganglia of the quail embryo. Dev Biol 1991; 147:451-9. 69. Sextier-Sainte-Claire Deville F, Ziller C, Le Douarin N. Developmental potentialities of cells derived from the truncal neural crest in clonal cultures. Brain Res Dev Brain Res 1992; 66:1-10. 70. Hagedorn L, Suter U, Sommer L. P0 and PMP22 mark a multipotent neural crestderived cell type that displays community effects in response to TGFbeta family factors. Development 1999; 126:3781-94. 71. Li HY, Say EH, Zhou XF. Isolation and characterization of neural crest progenitors from adult dorsal root ganglia. Stem Cells 2007; 25:2053-65.

©

20

08

LA

ND

ES

BIO

SC

IEN CE

.D

ON

10. Dupin E, Creuzet S, Le Douarin NM. The contribution of the neural crest to the vertebrate body. Adv Exp Med Biol 2006; 589:96-119. 11. Smith MM, Hall BK. Development and evolutionary origins of vertebrate skeletogenic and odontogenic tissues. Biol Rev Camb Philos Soc 1990; 65:277-373. 12. Joseph NM, Mukouyama YS, Mosher JT, Jaegle M, Crone SA, Dormand EL, Lee KF, Meijer D, Anderson DJ, Morrison SJ. Neural crest stem cells undergo multilineage differentiation in developing peripheral nerves to generate endoneurial fibroblasts in addition to Schwann cells. Development 2004; 131:5599-612. 13. Takashima Y, Era T, Nakao K, Kondo S, Kasuga M, Smith AG, Nishikawa S. Neuroepithelial cells supply an initial transient wave of MSC differentiation. Cell 2007; 129:1377-88. 14. Weston JA, Yoshida H, Robinson V, Nishikawa S, Fraser ST, Nishikawa S. Neural crest and the origin of ectomesenchyme: neural fold heterogeneity suggests an alternative hypothesis. Dev Dyn 2004; 229:118-30. 15. Baroffio A, Dupin E, Le Douarin NM. Clone-forming ability and differentiation potential of migratory neural crest cells. Proc Natl Acad Sci USA 1988; 85:5325-9. 16. Dupin E, Baroffio A, Dulac C, Cameron-Curry P, Le Douarin NM. Schwann-cell differentiation in clonal cultures of the neural crest, as evidenced by the anti-Schwann cell myelin protein monoclonal antibody. Proc Natl Acad Sci USA 1990; 87:1119-23. 17. Baroffio A, Dupin E, Le Douarin NM. Common precursors for neural and mesectodermal derivatives in the cephalic neural crest. Development 1991; 112:301-5. 18. Trentin A, Glavieux-Pardanaud C, Le Douarin NM, Dupin E. Self-renewal capacity is a widespread property of various types of neural crest precursor cells. Proc Natl Acad Sci USA 2004; 101:4495-500. 19. Calloni GW, Glavieux-Pardanaud C, Le Douarin NM, Dupin E. Sonic Hedgehog promotes the development of multipotent neural crest progenitors endowed with both mesenchymal and neural potentials. Proc Natl Acad Sci USA 2007; 104:19879-884. 20. Jiang Y, Jahagirdar BN, Reinhardt RL, Schwartz RE, Keene CD, Ortiz-Gonzalez XR, Reyes M, Lenvik T, Lund T, Blackstad M, Du J, Aldrich S, Lisberg A, Low WC, Largaespada DA, Verfaillie CM. Pluripotency of mesenchymal stem cells derived from adult marrow. Nature 2002; 418:41-9. 21. Jiang Y, Vaessen B, Lenvik T, Blackstad M, Reyes M, Verfaillie CM. Multipotent progenitor cells can be isolated from postnatal murine bone marrow, muscle, and brain. Exp Hematol 2002; 30:896-904. 22. Zipori D. The nature of stem cells: state rather than entity. Nat Rev Genet 2004; 5:873-8. 23. Anderson DJ. The neural crest cell lineage problem: neuropoiesis? Neuron 1989; 3:1-12. 24. Till JE, Mc CE. A direct measurement of the radiation sensitivity of normal mouse bone marrow cells. Radiat Res 1961; 14:213-22. 25. Metcalf D. Haematopoietic cells. Amsterdam; North Holland, 1971. 26. Spangrude GJ, Heimfeld S, Weissman IL. Purification and characterization of mouse hematopoietic stem cells. Science 1988; 241:58-62. 27. Uchida N, Weissman IL. Searching for hematopoietic stem cells: evidence that Thy-1.1lo Lin- Sca-1+ cells are the only stem cells in C57BL/Ka-Thy-1.1 bone marrow. J Exp Med 1992; 175:175-84. 28. Cohen AM, Konigsberg IR. A clonal approach to the problem of neural crest determination. Dev Biol 1975; 46:262-80. 29. Sieber Blum M, Cohen AM. Clonal analysis of quail neural crest cells: they are pluripotent and differentiate in vitro in the absence of noncrest cells. Dev Biol 1980; 80:96-106. 30. Sieber Blum M, Sieber F. Heterogeneity among early quail neural crest cells. Brain Res 1984; 316:241-6. 31. Ito K, Sieber Blum M. In vitro clonal analysis of quail cardiac neural crest development. Dev Biol 1991; 148:95-106. 32. Stemple DL, Anderson DJ. Isolation of a stem cell for neurons and glia from the mammalian neural crest. Cell 1992; 71:973-85. 33. Ito K, Morita T, Sieber Blum M. In vitro clonal analysis of mouse neural crest development. Dev Biol 1993; 157:517-25. 34. Dupin E, Le Douarin NM. Retinoic acid promotes the differentiation of adrenergic cells and melanocytes in quail neural crest cultures. Dev Biol 1995; 168:529-48. 35. Lahav R, Dupin E, Lecoin L, Glavieux C, Champeval D, Ziller C, Le Douarin NM. Endothelin 3 selectively promotes survival and proliferation of neural crest-derived glial and melanocytic precursors in vitro. Proc Natl Acad Sci USA 1998; 95:14214-9. 36. Loring J, Glimelius B, Erickson C, Weston JA. Analysis of developmentally homogeneous neural crest cell populations in vitro. I. Formation, morphology and differentiative behavior. Dev Biol 1981; 82:86-94. 37. Artinger KB, Bronner Fraser M. Partial restriction in the developmental potential of late emigrating avian neural crest cells. Dev Biol 1992; 149:149-57. 38. Le Douarin NM, Dupin E. Multipotentiality of the neural crest. Curr Opin Genet Dev 2003; 13:529-36. 39. Sommer L. Growth factors regulating neural crest cell fate decisions. Adv Exp Med Biol 2006; 589:197-205. 40. Metcalf D, Nicola NA. The regulatory factors controlling murine erythropoiesis in vitro. Prog Clin Biol Res 1984; 148:93-105. 41. Sieber Blum M. Role of the neurotrophic factors BDNF and NGF in the commitment of pluripotent neural crest cells. Neuron 1991; 6:949-55. 42. Lee HY, Kleber M, Hari L, Brault V, Suter U, Taketo MM, Kemler R, Sommer L. Instructive role of Wnt/beta-catenin in sensory fate specification in neural crest stem cells. Science 2004; 303:1020-3.

1018

Cell Cycle



©

20

08

LA

ND

ES

BIO

SC

IEN CE

.D

ON

OT D

IST RIB

UT E

.

72. Sextier-Sainte-Claire Deville F, Ziller C, Le Douarin NM. Developmental potentials of enteric neural crest-derived cells in clonal and mass cultures. Dev Biol 1994; 163:141-51. 73. Kruger GM, Mosher JT, Bixby S, Joseph N, Iwashita T, Morrison SJ. Neural crest stem cells persist in the adult gut but undergo changes in self-renewal, neuronal subtype potential, and factor responsiveness. Neuron 2002; 35:657-69. 74. Fernandes KJ, McKenzie IA, Mill P, Smith KM, Akhavan M, Barnabe-Heider F, Biernaskie J, Junek A, Kobayashi NR, Toma JG, Kaplan DR, Labosky PA, Rafuse V, Hui CC, Miller FD. A dermal niche for multipotent adult skin-derived precursor cells. Nat Cell Biol 2004; 6:1082-93. 75. Sieber-Blum M, Grim M, Hu YF, Szeder V. Pluripotent neural crest stem cells in the adult hair follicle. Dev Dyn 2004; 231:258-69. 76. Tomita Y, Matsumura K, Wakamatsu Y, Matsuzaki Y, Shibuya I, Kawaguchi H, Ieda M, Kanakubo S, Shimazaki T, Ogawa S, Osumi N, Okano H, Fukuda K. Cardiac neural crest cells contribute to the dormant multipotent stem cell in the mammalian heart. J Cell Biol 2005; 170:1135-46. 77. Yoshida S, Shimmura S, Nagoshi N, Fukuda K, Matsuzaki Y, Okano H, Tsubota K. Isolation of multipotent neural crest-derived stem cells from the adult mouse cornea. Stem Cells 2006; 24:2714-22. 78. Pardal R, Ortega Saenz P, Duran R, Lopez Barneo J. Glia-like stem cells sustain physiologic neurogenesis in the adult mammalian carotid body. Cell 2007; 131:364-77. 79. Joannides A, Gaughwin P, Schwiening C, Majed H, Sterling J, Compston A, Chandran S. Efficient generation of neural precursors from adult human skin: astrocytes promote neurogenesis from skin-derived stem cells. Lancet 2004; 364:172-8. 80. Toma JG, McKenzie IA, Bagli D, Miller FD. Isolation and characterization of multipotent skin-derived precursors from human skin. Stem Cells 2005; 23:727-37. 81. Wong CE, Paratore C, Dours Zimmermann MT, Rochat A, Pietri T, Suter U, Zimmermann DR, Dufour S, Thiery JP, Meijer D, Beermann F, Barrandon Y, Sommer L. Neural crest-derived cells with stem cell features can be traced back to multiple lineages in the adult skin. J Cell Biol 2006; 175:1005-15.

www.landesbioscience.com

Cell Cycle

1019