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RESEARCH COMMUNICATION
1 Gene Center and Institute of Biochemistry, University of Munich, 81377 Munich, Germany; 2 Max-Planck-Institute of Immunobiology, 79108 Freiburg, Germany
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Abstract |
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 Top Abstract Results and DiscussionMaterials and methodsAcknowledgmentsReferences |
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-catenin activates the expression of endogenous Dll1 in fibroblastic cells. Thus, Wnt signaling can affect the Notch pathway by a LEF1-mediated regulation of Dll1.
[Keywords: Somitogenesis; LEF1/TCF; Wnt; Notch; Dll1]
Received August 11, 2004; revised version accepted September 28, 2004.
; Saga and Takeda 2001).
The segmental structure of somites is generated in a spatially periodic pattern that is determined by a temporal oscillation of the expression of genes (for review, see Pourquié 2003). In vertebrates, genes of the Notch–Delta signaling pathway, including the Notch-responsive HES transcription factors, the Notch ligand Delta-like (Dll), and the Notch antagonist lunatic fringe (Lnfg), have been found to cycle during somitogenesis (for review, see Pourquié 2003). A role of Notch signaling in the rostrocaudal patterning of somites and in the regulation of the oscillations of cycling genes was inferred from gene disruptions of RBPj
and Lnfg, as well as from transgenic expression of a dominant negative form of delta-like1 (Conlon et al. 1995; Hrabe de Angelis et al. 1997; Evrard et al. 1998; Zhang and Gridley 1998; Cordes et al. 2003). In addition, Wnt signaling has been implicated in the regulation of somitogenesis (Auleha et al. 2003). A reduction of Wnt3a expression in mice carrying a hypomorphic allele of Wnt3a, termed vestigial tail (vt), results in alterations of vertebrate identity and oscillating Notch activity (Greco et al. 1996; Ikeya and Takeda 2001; Auleha et al. 2003). These results and those of Wnt3a misexpression experiments have been interpreted to suggest a hierarchy of Wnt and Notch signaling, in which Wnt3a acts upstream of Notch signaling in the regulation of somitogenesis. However, the molecular link between Wnt signaling and Notch signaling remains unclear.
LEF1/TCF transcription factors have been identified as nuclear mediators of Wnt signaling that activate Wnt-responsive genes in association with -catenin (for review, see van Noort and Clevers 2002). Lef1 and Tcf1 are coexpressed in the PSM of developing mice, and the targeted inactivation of both genes resulted in the lack of paraxial mesoderm and in the generation of multiple neural tubes, phenotypes that are identical to those of the Wnt3a null mutation (Takada et al. 1994; Yoshikawa et al. 1997; Galceran et al. 1999). In contrast, the individual null mutations of Lef1 and Tcf1 show no apparent defect in mesoderm formation or somite patterning, consistent with a redundant function of the transcription factors in these processes (van Genderen et al. 1994; Verbeek et al. 1995). Therefore, neither the double null mutations nor the single null mutations provided an insight into the presumed role of these transcription factors in somitogenesis and segmental patterning.
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Results and Discussion |
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TopAbstractResults and DiscussionMaterials and methodsAcknowledgmentsReferences |
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-galactosidase (LacZ) gene had been inserted in-frame into the exon encoding the DNA-binding domain of LEF1. We have previously shown that this targeted mutation allows for the stable accumulation of a truncated form of LEF1 that can interact with -catenin but fails to bind DNA (Galceran et al. 2000). Moreover, we found that the truncated LEF1 protein interferes with the -catenin-dependent transcriptional activation by coexpressed TCF transcription factors in transfection assays, and we observed that the Lef1-gal mutation generates a more severe phenotype in hippocampus development than the null mutation of Lef1 (Galceran et al. 2000). However, the homozygous Lef1-gal mutation is not as severe as the Lef1-/-Tcf1-/- mutation and mice carrying these mutations die perinatally and at embryonic day 10.5 (E10.5), respectively (Galceran et al. 1999, 2000).
Analysis of the skeleton of newborn homozygous mutant Lef1-gal mice by Alcian blue/alizarin red staining showed that the vertebral column and the ribcage, derivatives of somites, are severely malformed (Fig. 1a–d). The number of vertebrae was reduced and many vertebrae were fused. The caudal region was shortened and the tail was reduced to a small curly stump. In addition, the mutants showed an overall decrease in the number of ribs, fusions, and bifurcations of the ribs, as well as a severe malformation of the sternum. These data suggest that LEF1/TCF transcription factors are not only involved in the generation, but also in the patterning, of paraxial mesoderm. Consistent with the expression of Lef1-gal in the developing limb buds and the early arrest of limb bud development in Lef1-/-Tcf1-/- embryos (Fig. 2A; Galceran et al. 1999), the forelimbs and hind-limbs were severely malformed in homozygous Lef1-gal mice, with a consistent reduction in the number of fingers (Fig. 1e,f; data not shown).
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gal gene and the morphology of the mutant mice at E9.5 (Fig. 2A). Whole-mount staining for LacZ activity in heterozygous Lef1-gal mice revealed expression in the PSM, the newly formed somites, and the forelimb buds (Fig. 2A, panel a), consistent with the previously described pattern of Lef1 mRNA expression (Oosterwegel et al. 1993; Galceran et al. 1999). Homozygous mutant Lef1-gal mice showed a severely deformed tail and a lack of segmented somites (Fig. 2A, panels a–d). However, homozygous Lef1-gal embryos have no extra neural tubes, which are formed at the expense of paraxial mesoderm in both Lef1-/-Tcf1-/- and Wnt3a-/- embryos (Takada et al. 1994; Yoshikawa et al. 1997; Galceran et al. 1999).
To further define these defects, we analyzed the expression of molecular markers that identify specific mesodermal cell populations and structures (Fig. 2B). Expression of Pax1, which is normally expressed in ventromedial cells of the sclerotome, is severely impaired in homozygous Lef1-gal mice in the region caudal of the forelimbs (Fig. 2B, panels a,b). As some thoracic skeletal elements are formed in the mutant mice, these data suggest that the formation of sclerotome is delayed and/or reduced. Likewise, expression of Pax3 showed a markedly reduced mesodermal expression in the mutant embryos (Supplementary Fig. 1c,d). We also examined the expression of two genes, Brachyury (T) and Axin2, that have been identified as direct targets for LEF1 and Wnt signaling (Yamaguchi et al. 1999; Galceran et al. 2001; Auleha et al. 2003). The expression of T was reduced in the anterior region of the PSM of homozygous Lef1-gal mice, in contrast to the complete lack of expression of T in Lef1-/-Tcf1-/- mice (Fig. 2B, panels c,d; Galceran et al. 2001). The expression of Axin2 was more severely affected in the PSM of homozygous Lef1-gal mice (Fig. 2B, panels e,f), whereas the expression of Wnt3a was normal (Supplementary Fig. 1e,f).
To examine the role of LEF1/TCF factors in the patterning of somites, we analyzed the developing peripheral nervous system in Lef1-gal mice at E11.5 by anti-neurofilament staining. Mutant mice showed a lack or misrouting of neural crest-derived spinal nerves that traverse the anterior compartment of somites in wild-type embryos (Fig. 3A, panels a,b; Supplementary Fig. 1g,h). Moreover, the mutant mice showed fusions of somites and a lack of expression of Semaphorin D, which is expressed normally in the posterior half of the dermomyotome (Supplementary Fig. 1k,l; Adams et al. 1996). With the aim of obtaining additional evidence for a defect in the patterning of somites, we analyzed the expression of the paired-type homeobox gene Uncx4.1, which is restricted to the posterior somite halves (Neidhardt et al. 1997), and Cerberus, cer1, which is expressed in the anterior halves of newly formed somites (Biben et al. 1998). In homozygous mutant mice, Uncx4.1 expression can be detected; however, the segmental pattern is abrogated caudal of the forelimb bud and the pattern is impaired in the cervical somites (Fig. 3A, panels c,d). The expression of Cerberus is virtually lost in the mutant mice (Fig. 3A, panel f). Together, these data confirm the defect of homozygous Lef1-gal mice in the rostrocaudal patterning of somites.
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). The Mesp2 gene, which encodes a transcription factor that is expressed in the anterior PSM, is important for somite boundary formation and the establishment of rostrocaudal polarity (Saga et al. 1997). Mesp2 antagonizes the expression of Uncx4.1 and is involved in a complex feedback regulation with Dll1 (Takahashi et al. 2003). In addition, Notch1 and Dll1 are important for the rostrocaudal polarity and the oscillation of cycling genes (for review, see Pourquié 2003). Expression analysis of these genes in homozygous Lef1-gal mice showed a marked reduction in the expression of Mesp2, Notch1, and Dll1 (Fig. 3B, panels a–f). In addition, we observe a decrease in the expression of Lnfg in the newly formed somites of mutant embryos (Fig. 3B, panels g,h). The reduction of the expression of multiple markers of rostrocaudal polarity could be interpreted to suggest that LEF1/TCF proteins regulate several genes in the Notch/Delta/Mesp2 pathway and/or that a LEF1/TCF-regulated gene is involved in genetic interactions with other components of the pathway. We favor the first view because the phenotype of the homozygous Lef1-gal mice differs from those of both Mesp2-/- and Dll1-/- mice. Mesp2-/- mice show an expansion of Dll1 expression and a caudalization of somites, (Saga et al. 1997), whereas Dll1-null embryos show a rostralization of somites (del Barco Barrantes et al. 1999). In contrast, the homozygous Lef1-gal mice show defects in both patterning events.
The marked decrease in the expression of Notch1 and Dll1 in homozygous Lef1-gal mice is consistent with the proposed hierarchy of the Wnt and Notch signaling pathways, and this raised the possibility that components of the Notch pathway are directly regulated by LEF1/TCF factors. To this end, we examined the promoter regions of these genes for the presence of potential LEF1/TCF-binding sites. The 5'-flanking regions of both Notch1 and Dll1 genes were found to contain multiple potential LEF1/TCF-binding sites (Fig. 4A; data not shown). Previous transgenic analysis of the transcriptional regulatory sequences of the Dll1 gene identified distinct elements that direct gene expression in the paraxial mesoderm and nervous system (Beckers et al. 2000). Two sequence homology domains (HDs) were found to confer neuronal expression, whereas a 1.5-kb region that resides between the HDs acts as a mesoderm-specific enhancer. In addition, a 1.6-kb region that includes the transcription start site directs expression in the paraxial mesoderm and in developing somites. The LEF1-binding sites in Dll1 were confirmed as bona fide binding sites by electrophoretic mobility shift assays, using recombinant LEF1 protein and radiolabeled oligonucleotides (Fig. 4B; Supplementary Fig. 2).
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-galactosidase (LacZ) gene (Fig. 4C). Six out of 18 transgenic embryos expressed the Dll1–wt–LacZ gene in the PSM and somites (Fig. 4D,E). In contrast, the expression of mutant transgenes carrying point mutations in two or three LEF1-binding sites was markedly impaired in the PSM (Fig. 4D,E). Only 1/26 and 2/17 embryos carrying the Dll1–mt1–LacZ and Dll1–mt2–LacZ transgenes, respectively, showed expression in the PSM. However, the expression of the mutant transgenes in the somites was similar to that of the wild-type transgene. These data indicate that the activity of the Dll1 promoter in the PSM, but not in the somites, is dependent on the LEF1-binding sites.
To obtain further evidence for the regulation of Dll1 by LEF1, we examined whether the induced expression of a LEF1–-catenin fusion protein, in which the C-terminal activation domain of -catenin is linked to the N terminus of LEF1 (Fig. 5A; Hsu et al. 1998), results in the expression of endogenous Dll1 in a fibroblastic cell line. We have previously shown that the LEF–-catenin fusion protein activates Wnt-response elements in the absence of a Wnt signal (Hsu et al. 1998). We generated a stably transfected cell line (NIH-BC29), in which the catC–Lef1 gene had been linked to ecdysone-response elements. Within 12 h after treating the cells with Ponasterone (No et al. 1996), catC–LEF protein could be detected by immunoblot analysis (Fig. 5B). Quantitative RT–PCR assays confirmed a 12-fold increase of catC–Lef1 transcripts and showed an eight- and threefold increase in the levels of expression of endogenous Dll1 and Axin2 genes, respectively (Fig. 5C). This increase in Dll1 expression is somewhat modest, given the multiplicity of LEF1-binding sites, and suggests the possibility that the regulation of Dll1 by LEF1 in vivo requires the cooperation with another transcription factor. TBX6 has been shown to participate in the regulation of Dll1 (White et al. 2003), and in an independent study, the labs of Gossler and Herrmann have found that LEF1 and TBX6 collaborate in the regulation of Dll1 (Hofmann et al. 2004).
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-LEF1 antibodies. We also examined whether endogenous LEF1 is bound to Dll1 regulatory sequences by performing ChIP experiments with chromatin from PSM of wild-type E9.5 embryos (Fig. 5F). These experiments indicated that LEF1 binds to multiple sites in both enhancer and promoter of Dll1 in vivo.
Taken together, these data suggest that Wnt-responsive transcription factors of the LEF1/TCF family are involved in a direct regulation of Dll1, thus providing a molecular link between the Wnt and Notch signaling pathways in somitogenesis (Fig. 5G). LEF1/TCF proteins have been shown to directly regulate Fgf4 in epithelial–mesenchymal interactions during tooth development (Kratochwil et al. 2002), and LEF1 protein has been found to interact and functionally collaborate with BMP/TGF-responsive Smad proteins (Labbe et al. 2000; Nishita et al. 2000). Thus, Wnt signaling can interact via LEF1/TCF transcription factors with multiple signaling pathways, which may help to diversify the biological effects of Wnt signaling.
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Materials and methods |
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TopAbstractResults and DiscussionMaterials and methodsAcknowledgmentsReferences |
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The region of Dll1 residing between -1631 and -7 upstream of the translation initiation codon, which includes the mesoderm-specific promoter and transcription start site (Beckers et al. 2000), was obtained by PCR amplification and cloned into phsp68–LacZpA, from which the hsp promoter was removed (Kothary et al. 1989). Oligonucleotide-directed point mutations in LEF1-binding sites were introduced by using the QuikChange Kit (Stratagene).
For the generation of a cell line in which a Wnt-independent form of LEF1 can be induced, NIH-3T3 cells were stably transfected with a regulator vector pVgRXR (Invitrogen) and subsequently with a gene construct, in which the C-terminal activation domain of -catenin was fused with the N terminus of LEF1 (Hsu et al. 1998). The catC–Lef1 gene was linked to ecdysone-responsive elements, allowing for the induction of expression by treatment of the cells with 30 µM Ponasterone (No et al. 1996).
Knockout and transgenic mice, skeletal preparation, and whole-mount in situ hybridizations
The construction of the targeted insertion of the bacterial lacZ gene into the genomic Lef1 locus and the generation of Lef1-gal mice is described in Galceran et al. (2000). Transgenic mice were generated with Dll1–LacZ gene constructs and genotyped by PCR of yolk sac DNA, and the expression of the transgene was analyzed by staining for -galactosidase activity in E8.5 and E9.5 embryos. Alcian blue/alizarin red skeletal staining was performed according to standard procedures. Whole-mount in situ hybridizations were performed with digoxigenin-labeled antisense riboprobes as described in Galceran et al. (1999).
Electrophoretic mobility shift assay
DNA-binding assays were performed by an electrophoretic mobility shift assay with purified recombinant LEF1 protein as described (Galceran et al. 2001). The binding reaction contained 100 ng of purified His-6-tagged LEF1 protein, 2 fmol of 5' end-labeled double-stranded oligonucleotide, and 10 mg/mL poly(dI-dC). The binding reactions were performed in the absence or presence of 100-fold molar excess of unlabeled competitor DNA. The nucleotide sequences of the probes are in Supplementary Table 1A.
Chromatin immunoprecipitations
NIH-BC29 cells (5 x 107) or PSM from 40 embryos at E9.5 were prepared and fixed 10 min with 1% formaldehyde in PBS at 37°C. Cross-linking was stopped by addition of glycine to a final concentration of 0.125 M. Cells were dispersed and nuclei prepared by addition of hypotonic buffer (10 mM Tris-Cl, 10 mM NaCl, 0.2% NP-40). Cross-linked chromatin was sonicated and after reversal of the cross-links, 50 µg chromatin was immunoprecipitated with anti-LEF1 antibodies, as described (Frank et al. 2001). Specific Dll1 sequences were detected by semiquantitative PCR with primers flanking LEF1-binding sites or gene-internal regions, using threefold dilutions of template DNA. The amplifications of BC29 template DNA involved 32 cycles, followed by hybridization with radiolabeled oligonucleotides and detection by phosphorimager. DNA from PSM was amplified by 40 cycles and the products were visualized by ethidium bromide staining. The sequences of the primers are provided in Supplementary Table 1B.
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Acknowledgments |
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TopAbstractResults and DiscussionMaterials and methodsAcknowledgmentsReferences |
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Footnotes |
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Article and publication are at http://www.genesdev.org/cgi/doi/10.1101/gad.1249504.
3 Present address: Instituto de Neurociencias, Campus San Juan, 03550 Sant Joan d'Alacant, Spain 
4 Corresponding author. E-MAIL grosschedl{at}immunbio.mpg.de; FAX 49-761-5108-799.
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 D. Medici, E. D. Hay, and D. A. Goodenough Cooperation between Snail and LEF-1 Transcription Factors Is Essential for TGF-beta1-induced Epithelial-Mesenchymal Transition Mol. Biol. Cell, April 1, 2006; 17(4): 1871 - 1879. [Abstract] [Full Text] [PDF]
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W. Satoh, T. Gotoh, Y. Tsunematsu, S. Aizawa, and A. Shimono Sfrp1 and Sfrp2 regulate anteroposterior axis elongation and somite segmentation during mouse embryogenesis Development, March 15, 2006; 133(6): 989 - 999. [Abstract] [Full Text] [PDF]
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S. M. Ghogomu, S. van Venrooy, M. Ritthaler, D. Wedlich, and D. Gradl HIC-5 Is a Novel Repressor of Lymphoid Enhancer Factor/T-cell Factor-driven Transcription J. Biol. Chem., January 20, 2006; 281(3): 1755 - 1764. [Abstract] [Full Text] [PDF]
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M.-a. Nakaya, K. Biris, T. Tsukiyama, S. Jaime, J. A. Rawls, and T. P. Yamaguchi Wnt3alinks left-right determination with segmentation and anteroposterior axis elongation Development, December 15, 2005; 132(24): 5425 - 5436. [Abstract] [Full Text] [PDF]
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J. Deschamps and J. van Nes Developmental regulation of the Hox genes during axial morphogenesis in the mouse Development, July 1, 2005; 132(13): 2931 - 2942. [Abstract] [Full Text] [PDF]
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V. Devgan, C. Mammucari, S. E. Millar, C. Brisken, and G. P. Dotto p21WAF1/Cip1 is a negative transcriptional regulator of Wnt4 expression downstream of Notch1 activation Genes & Dev., June 15, 2005; 19(12): 1485 - 1495. [Abstract] [Full Text] [PDF]
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H. Lickert, B. Cox, C. Wehrle, M. M. Taketo, R. Kemler, and J. Rossant Dissecting Wnt/{beta}-catenin signaling during gastrulation using RNA interference in mouse embryos Development, June 1, 2005; 132(11): 2599 - 2609. [Abstract] [Full Text] [PDF]
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A. Kawamura, S. Koshida, H. Hijikata, T. Sakaguchi, H. Kondoh, and S. Takada Zebrafish Hairy/Enhancer of split protein links FGF signaling to cyclic gene expression in the periodic segmentation of somites Genes & Dev., May 15, 2005; 19(10): 1156 - 1161. [Abstract] [Full Text] [PDF]
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