Correspondence to Lukas Sommer: sommer{at}cell.biol.ethz.ch
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Introduction |
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Recently we have described an early population of neural crest stem cells (eNCSCs) that is highly homogeneous with respect to marker expression and the potential to generate autonomic and sensory neurons, glia, and smooth muscle cells (Lee et al., 2004). Clonal cell culture experiments revealed the responsiveness of these cells to several instructive growth factors that promote the generation of specific cell fates at the expense of other possible fates. These factors include members of the TGFß factor family that promote autonomic neurogenesis and the development of smooth musclelike cells, neuregulin1 (NRG1) isoforms that induce the generation of peripheral glia, and Wnt signaling that promotes sensory neurogenesis in a ß-catenindependent manner (Le Douarin and Dupin, 2003; Kléber and Sommer, 2004). In vivo and in cell culture, eNCSCs that lack the Wnt signaling component ß-catenin fail to generate sensory neurons (Hari et al., 2002). Complementary to this, embryos that express a constitutively active form of ß-catenin specifically in NCSCs generate almost exclusively sensory neural cells at the expense of other possible neural crestderived lineages (Lee et al., 2004). Thus, unlike in other stem cell types, canonical Wnt signaling on its own does not support stem cell expansion in NCSCs, but rather promotes sensory neurogenesis. So far, the signals supporting NCSC maintenance and self-renewal have not been identified, although it has been possible to passage both migratory and postmigratory NCSCs for some generations in a nondefined medium (Stemple and Anderson, 1992; Bixby et al., 2002).
Given the expression of Wnts in the dorsal neural tube at the time of neural crest emigration and the sensitivity of almost all eNCSCs to Wnt signaling (Parr et al., 1993; Lee et al., 2004), the question arises as to why during normal development only some cells adopt a sensory neural fate as they emigrate while other neural crest cells remain multipotent and can contribute to multiple nonsensory neural crest derivatives (Kléber and Sommer, 2004). Similarly, it remains to be shown why bone morphogenic proteins (BMPs) that are able to induce autonomic neurogenesis (Reissmann et al., 1996; Shah et al., 1996) and that are secreted by the ectoderm and the dorsal neural tube (Liem et al., 1995) do not lead to the generation of autonomic neurons in neural crest cells immediately after their delamination from the neural tube. Convergence of BMP and canonical Wnt signaling has been reported in several studies (Nelson and Nusse, 2004). We therefore investigated whether BMP and Wnt might act in a mutually antagonistic fashion to suppress neurogenesis in NCSCs. We find that combinatorial Wnt/BMP signaling not only suppresses differentiation of NCSCs, but also acts synergistically to maintain stem cell multipotency.
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Results |
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Maintenance of NCSC markers and suppression of differentiation by combined Wnt and BMP signaling
To further address the interaction between Wnt and BMP signaling, we exposed explant cultures of wild-type neural crest cells to either Wnt1, BMP2, or both of these factors. While BMP2 alone induced the generation of ganglia-like structures consisting of NF+/Brn-3A autonomic neurons (Fig. 3, A, D, and G), exposure of neural crest explants to Wnt1 led to the formation of ganglia containing NF+/Brn-3A+ sensory neurons (Fig. 3, B, E, and H). Wnt1-induced sensory neurons were located close to the neural tube (mean distance to neural tube: 58.7 ± 14.7 µm), whereas BMP2-induced autonomic neurons developed distal to the neural tube (mean distance to neural tube: 287.0 ± 58.7 µm), reflecting the localization of sensory and autonomic ganglia in vivo. Intriguingly, the simultaneous application of BMP2 and Wnt1 to neural crest cells prevented the development of NF-expressing neurons, and no ganglia-like structures were present in these cultures (Fig. 3, C and F). This was not simply due to the loss of neural crest cells or impaired migration because many Sox10-positive neural crest cells were detectable in Wnt1/BMP2-treated explant cultures (Fig. 3, F, I, K, and L). These data indicate that the combined activity of Wnt1 and BMP2 suppresses both autonomic and sensory neuron formation. Moreover, Wnt1/BMP2 actively supported maintenance of Sox10-positive cells because in the absence of both growth factors neural crest cells either die or differentiate within a few days in the chosen culture conditions (not depicted; Lee et al., 2004).
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Combined Wnt and BMP signaling instructively promotes NCSC maintenance and factor responsiveness
The lack of apparent neurogenesis and gliogenesis upon treatment of neural crest cells with Wnt1 plus BMP2 could indicate a selective elimination of neural crest cells as they undergo differentiation. Alternatively, our data could reflect an instructive role of combined Wnt and BMP signaling on individual eNCSCs to maintain expression of stem cell markers while preventing their differentiation. To distinguish between these possibilities, explants of neural crest cells were replated at clonal density, individual eNCSCs were prospectively identified by virtue of their p75 expression (Stemple and Anderson, 1992), and their developmental potential was assessed by challenging them with either Wnt1, BMP2, or a combination of both factors. On sister dishes, 92.1 ± 1.9% of all p75-positive cells also expressed Sox10 (Fig. 4 A). In agreement with our previous findings (Lee et al., 2004), exposure of p75-labeled cells to Wnt1 alone induced the formation of clones containing Brn-3Apositive sensory neurons in 83.1 ± 5.8% of all eNCSCs (Fig. 4, B and E), whereas upon BMP2 treatment 85.4 ± 5.7% of all eNCSCs adopted an autonomic fate marked by Mash-1 (Fig. 4, C and F). In contrast, combined application of Wnt1 and BMP2 suppressed both sensory and autonomic neurogenesis in eNCSCs, so that only very few or no sensory and autonomic cells were produced in these conditions (0.8 ± 1.4% and 0 ± 0%, respectively). Instead, 84.9 ± 5.9% of all eNCSCs challenged with Wnt1 plus BMP2 continued to express Sox10 (Fig. 4, D and E). Furthermore, cell death was minimal in all clonal experiments, excluding selective effects of Wnt and BMP signaling. Thus, the combined activities of Wnt1 and BMP2 do not selectively eliminate neuronal progenitors, but rather instructively promote maintenance of the NCSC marker Sox10 in the vast majority of all NCSCs. Moreover, although cells proliferated less than in the presence of BMP2 alone, 51.9 ± 11.2% of the Wnt1/BMP2-treated cells divided once or more times (Fig. 4 G), indicating that combined Wnt and BMP signaling also supports self-renewal of Sox10-positive NCSCs.
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Loss of Wnt responsiveness in NCSCs over time
Although NCSCs that had been maintained in culture were sensitive to various instructive growth factors, their response to the sensory neuroninducing activity of Wnt1 was clearly reduced when compared with the response of eNCSCs emigrating from the neural tube. Possibly, maintenance of NCSCs in culture leads to loss of their Wnt responsiveness with time. To address this issue, Wnt1/BMP2-treated NCSCs were replated at clonal density, as described in the previous paragraph, and exposed to Wnt1 alone. In contrast to single eNCSCs (Fig. 4), only 13.5 ± 3.7% of all maintained NCSCs generated sensory neuroncontaining clones while the remaining cells displayed no obvious response to Wnt1 (Fig. 6, A and B; Table I). This finding might represent a cell culture artifact with no relevance to neural crest development in vivo. Alternatively, the change in Wnt1 responsiveness of NCSCs might reflect processes also occurring in vivo. Cells with NCSC features persist during development in various postmigratory targets of the neural crest, including the sciatic nerve and the dorsal root ganglia (DRG) (Hagedorn et al., 1999; Bixby et al., 2002). To assess whether Wnt1 could induce sensory neurogenesis in postmigratory NCSCs present at later developmental stages, NCSCs were isolated either from the sciatic nerve or from the DRG at embryonic day 12 (E12), plated at clonal density, prospectively identified by p75 labeling, and incubated with or without Wnt1. Previous studies have shown that 7090% of the undifferentiated p75-positive neural crest cells present in the sciatic nerve and in the DRG at these developmental stages are sensitive to the instructive activities of TGFß, NRG1, and BMP2 (not depicted; Hagedorn et al., 1999; Bixby et al., 2002). However, in contrast to migratory eNCSCs, neither sciatic nerve nor DRG-derived NCSCs were able to undergo increased sensory neurogenesis in response to Wnt1 (Fig. 6, C and D), indicating changes in Wnt signal interpretation that have been acquired over time in vivo.
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Discussion |
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Stem cell maintenance and early sensory lineage segregation in emigrating neural crest cells
Although in culture emigrating eNCSCs initially represent a homogeneous cell population with respect to their potentials (Lee et al., 2004), the cells quickly undergo lineage segregation (Henion and Weston, 1997; Greenwood et al., 1999; Luo et al., 2003). This is likely due to the limited signaling range and activity of growth factors such as neural tubederived Wnt that in explant cultures induces sensory neurogenesis in a subset of all neural crest cells and that can be modulated by BMP signaling (Figs. 1 and 2). Likewise, in vivo the migratory neural crest is heterogeneous as has been shown by single-cell tracing experiments (Fraser and Bronner-Fraser, 1991). Although some of the labeled cells in these experiments contributed to both sensory and autonomic ganglia, others were restricted and generated either only sensory or only sympathetic cells. Moreover, Ngn2-positive cells fated predominantly for sensory ganglia are found in neural crest cells as they emigrate from the neural tube, intermingled with multifated Sox10-positive cells (Zirlinger et al., 2002). Thus, maintenance vs. sensory lineage segregation is regulated very early in neural crest development. Based on our data, we propose (Fig. 7) that neural crest cells emerge from the neural tube with equal competence; combinatorial Wnt and BMP signaling maintains multipotency in some emigrating NCSCs and suppresses their neuronal specification, whereas other emigrating neural crest cells are not (or at least not continuously) exposed to the synergistic activity of Wnt plus BMP and adopt a Wnt-dependent sensory fate. How this cellular heterogeneity is established remains elusive. Possibly, restricted signal availability or factors locally inhibiting BMP activity might be involved. Moreover, it is presently not clear whether Wnt/BMP signaling maintains NCSCs with potentials exceeding smooth muscle formation, neurogenesis, and gliogenesis. In particular, recent evidence indicates that the melanocyte lineage segregates from other neural crest lineages already in the neural tube, before neural crest emigration (Wilson et al., 2004). In any case, however, our finding that BMP signaling can counteract the sensory neuroninducing activity of canonical Wnt signaling provides one conceivable solution to the paradox that in normal neural crest development not all emigrating neural crest cells adopt a sensory fate, despite the general responsiveness of eNCSCs to Wnt signaling and the expression of Wnts at the site of neural crest delamination. Similarly, the inhibition of BMP-dependent autonomic neurogenesis by Wnt signaling also offers an explanation for why the generation of autonomic neurons is prevented in emigrating neural crest cells in spite of the presence of BMPs in the ectoderm and the dorsal neural tube.
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Although Wnt in combination with BMP signaling maintains multipotency of NCSCs and supports cell division in many of these cells, their responsiveness to instructive growth factors changes with time. Most intriguingly, expanded NCSCs lose their sensitivity to the sensory neuroninducing activity of canonical Wnt signaling while remaining responsive to other instructive growth factors including BMP2, NRG1, and TGFß. The loss of Wnt responsiveness cannot be explained by the selective elimination of cells with sensory potential, as demonstrated by clonal analysis of cells that have been maintained in the presence of Wnt1 and BMP2 (Figs. 5 and 6). Rather, during maintenance in culture individual NCSCs have acquired intrinsic differences as compared with eNCSCs emigrating from the neural tube. Strikingly, these changes correspond to processes occurring in vivo: Although in the case of sciatic nerve cells increased cell death might have masked an effect of Wnt on sensory neurogenesis, postmigratory NCSCs present in both the sciatic nerve and the DRG displayed an altered Wnt response as compared with migratory NCSCs and failed to generate sensory neurons (Fig. 6). Similar changes also occur in response to other growth factors, both in NCSCs isolated at different time points and in postmigratory NCSCs derived from different PNS regions (Bixby et al., 2002; Kruger et al., 2002). Thereby, changes in cell-intrinsic determinants influence cell fate decisions by changing the sensitivity of neural crest cells to specific extracellular signals (White et al., 2001; Kubu et al., 2002). For instance, the level of the transcription factor Sox10 determines how neural crest cells interpret their environment and which fate they adopt (Paratore et al., 2001). Such changes acquired over time might also explain the various functions attributed to Wnts and BMPs during neural crest development, ranging from neural crest induction, delamination, and NCSC expansion to melanocyte formation and neurogenesis (Ikeya et al., 1997; Dorsky et al., 1998; Garcia-Castro et al., 2002; Burstyn-Cohen et al., 2004; Lee et al., 2004). Indeed, blocking Wnt signaling at various time points in zebrafish embryogenesis indicated its reiterated but distinct roles in neural crest development (Lewis et al., 2004).
Neural stem cells from the CNS also undergo intrinsic changes during development, biasing a cell to self-renew, to generate either neurons or glia, or to produce specific neuronal cell types (Alvarez-Buylla et al., 2001). In particular, canonical Wnt signaling promotes stem cell expansion at early stages of cortical development, whereas it induces neuronal lineage commitment at later stages (Hirabayashi et al., 2004). Thus, as is the case with NCSCs found at different stages of PNS development, the proposed transition from neural stem cells present in the embryo to adult neural stem cells is accompanied by alterations in the stem cell's genetic program (Alvarez-Buylla et al., 2001). It follows that continuous self-renewal used as a key feature of stem cells might not apply in its strictest sense to neural (and conceivably other) stem cells during development. Rather, although maintaining their multipotency, stem cells adapt to signals present in their extracellular environment.
The environment, however, also changes with time. In the PNS, canonical Wnt activity is observed only at early development stages, when neural crest cells emigrate from the neural tube (Fig. 6). At later stages, Wnt/ß-catenin activity was no longer detectable in neural crestderived tissues, such as DRG, peripheral nerves, and sympathetic ganglia. Thus, not only do NCSCs lose their Wnt responsiveness with time, but also postmigratory neural crest cells are not exposed to canonical Wnt signaling any more. We propose that this dual regulation of Wnt signaling ensures the tight control, both spatially and temporally, of NCSC maintenance by Wnt/BMP and sensory lineage segregation by Wnt signaling alone. Consequently, late sensory neurogenesis in the forming DRG may occur in a Wnt-independent manner. Likewise, maintenance of NCSCs at later stages may be regulated by cues not involving canonical Wnt signaling. Alternatively, transient priming of NCSCs by Wnt plus BMP at early stages may be sufficient to maintain NCSCs also at later stages until they are exposed to new instructive cues, such as BMPs that are expressed in the dorsal aorta and induce autonomic neurogenesis (Reissmann et al., 1996; Shah et al., 1996). In sum, NCSC maintenance and lineage decisions appear to be regulated by the dynamic interaction between cell-intrinsic properties and cell-extrinsic cues, including Wnt signaling, that change with time and location.
Combinatorial Wnt and BMP signaling
Our study provides multiple lines of evidence for a cross-talk between Wnt and BMP signaling in eNCSCs. Wnt1 treatment as well as sustained ß-catenin activity interferes with the autonomic neuroninducing activity of BMP2 (Figs. 2 and 3). Likewise, BMP signaling suppresses ß-catenindependent sensory neurogenesis from eNCSCs (Fig. 2) and prevents sensory neuron formation in eNCSCs treated with exogenous Wnt1 (Fig. 3). The fact that BMP2 also blocks sensory neurogenesis in eNCSCs expressing a constitutively active form of ß-catenin indicates that BMP signal transduction interacts with canonical Wnt signaling at the level of or downstream of ß-catenin. Strikingly, the cross-talk between Wnt and BMP signaling is not just mutually antagonistic but synergistic, leading to a new fate not seen with the individual signals alone. Indeed, combined Wnt and BMP signaling suppresses also glial and nonneural cell differentiation, apart from sensory and autonomic neurogenesis, while maintaining stem cell features in neural crest cells.
Wnt/ß-catenin signaling interacts with several other signal transduction pathways, which influences its signaling output (Nelson and Nusse, 2004). In particular, Wnt and BMP signaling cooperate in various species in either a synergistic or antagonistic manner to regulate cell lineage decisions, patterning, or tumorigenesis. Thereby, the ß-catenin/Lef/TCF transcription factor complex acts as signal coordinator that physically interacts with the BMP signaling components SMAD4 or SMAD1 to induce specific target genes. Most recently, BMP has been shown to antagonize Wnt/ß-catenin in intestinal stem cells by signaling through the tumor suppressor PTEN and Akt kinase (He et al., 2004). Intriguingly, in these stem cells Wnt promotes self-renewal and Wnt/BMP promotes cell fate decisions, unlike in NCSCs, indicating that the effects of Wnt signaling and Wnt signal modulation by BMP are dependent on the stem cell type (Kléber and Sommer, 2004).
The signaling components involved and the target genes of Wnt/BMP signal convergence in NCSCs remain to be identified. The homeodomain factor Msx2 might possibly be implicated, at least in the cranial crest, because Msx2 expression is regulated by cooperative Wnt/BMP signaling in embryonic stem cells (Hussein et al., 2003) and suppresses chondrogenic differentiation in migratory cranial neural crest cells (Takahashi et al., 2001). Another candidate transcription factor is Sox10, which is persistently expressed in NCSCs maintained by Wnt1 plus BMP2 (Figs. 35). Similar to the combinatorial activity of Wnt and BMP, Sox10 promotes maintenance of multipotency and growth factor responsiveness in cultured NCSCs (Kim et al., 2003), and is required for maintenance of enteric NCSCs in vivo (Paratore et al., 2002). Although there is precedence for Wnt/ß-catenin signaling regulating expression of Sox genes (Blache et al., 2004), a functional interplay between Sox10 and the canonical Wnt signaling pathway might take place at the protein level, as several Sox proteins physically interact with ß-catenin (Zorn et al., 1999; Akiyama et al., 2004; Sinner et al., 2004). It is open whether such interactions occur in NCSCs, but they might play a part in the modulation of the signaling network provided by Wnt and BMP that controls NCSC maintenance and cell fate decisions.
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Materials and methods |
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Neural crest explant cultures
Mouse neural crest explant cultures under conditions permissive for sensory neurogenesis were performed as reported previously (Hari et al., 2002; Lee et al., 2004). To inhibit sensory neurogenesis, early neural crest explants were supplemented with 50 ng/ml BMP2 (R&D Systems). Exposure of neural crest cells to Wnt1-expressing and control fibroblasts was done as described previously (Lee et al., 2004). In some experiments, neural crest cells on fibroblast monolayers were treated with BMP2 20 h after emigration and cultured for an additional 512 d. To challenge Wnt1/BMP2-treated NCSCs after 5 d in explant culture, cells were washed three times in Dulbecco's minimum essential medium and cultured for an additional 7 d either in defined medium (Greenwood et al., 1999) supplemented with 125 ng/ml noggin (R&D Systems) or in medium containing chicken embryo extract (Stemple and Anderson, 1992) supplemented with 20 ng/ml IGF-1 (R&D Systems) and either 50 ng/ml BMP2, 0.1 ng/ml TGFß1 (R&D Systems), or 1 nM NRG1 (R&D Systems). The number of sensory neurons (mean ± SD) was determined for three different explants, counting at least 2,000 cells per explant. Five ganglia per explant in at least three different explants were assayed to quantify the mean distances between ganglia and neural tube, using NIH Image 1.62 software.
Clonal analysis of NCSCs
Rat eNCSCs and postmigratory NCSCs from rat DRG and sciatic nerve were prepared as reported previously (Hagedorn et al., 1999; Leimeroth et al., 2002; Lee et al., 2004). Clonal analysis of prospectively identified NCSCs plated onto Wnt1-expressing or control fibroblast monolayers was done as in Lee et al. (2004). The plating efficiency was 6070%. Some cultures on fibroblast monolayers were supplemented with 50 ng/ml BMP2 (R&D Systems) 2 d after plating. To evaluate maintenance of multipotency, rat NCSCs were incubated on Wnt1-expressing monolayers in the presence of BMP2 for 11 d. After 11 d, the remaining fibroblasts and neural tubes were removed and the explants were replated at clonal density onto freshly prepared Wnt1-expressing or control feeder monolayers, or onto pdL/fibronectin-coated plates. Clone founder cells were identified and mapped as explained above. Cells exposed to Wnt1 were cultured in medium permissive for sensory neurogenesis (Lee et al., 2004). Cultures in the absence of Wnt1 were treated with 50 ng/ml BMP2 (R&D Systems), 0.1 ng/ml TGFß (R&D Systems), or 1 nM NRG1 (R&D Systems) for 4, 5, and 7 d, respectively, in medium containing chicken embryo extract (Stemple and Anderson, 1992).
Immunocytochemistry
Anti-p75, anti-Sox10, anti-Brn-3A, and anti-NF160 antibody stainings were done as in Hari et al. (2002). Anti-GFAP and anti-S100 stainings were performed using pAbs (each at 1:200 dilution; DakoCytomation). SMA was stained with an mAb (1:400 dilution; Sigma-Aldrich); for Mash-1 staining, cells were incubated with an mAb (1:100 dilution; BD Biosciences) overnight at 4°C, followed by incubation with a HRP-coupled antimouse IgG antibody (1:200 dilution; DakoCytomation) and by HRP development using DAB as substrate. Immunofluorescence was analyzed using an Axiovert 100 microscope and AxioVision 4.1 software (Carl Zeiss MicroImaging, Inc.).
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Acknowledgments |
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Supported by grants of the Swiss National Science Foundation, the National Center of Competence in Research "Neural Plasticity and Repair," and the Swiss Federal Institute of Technology.
Submitted: 16 November 2004
Accepted: 7 March 2005
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References |
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