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. 2007 Jul 13;8(8):784–789. doi: 10.1038/sj.embor.7401030

Expression of Msgn1 in the presomitic mesoderm is controlled by synergism of WNT signalling and Tbx6

Lars Wittler 1,2, Eun-ha Shin 1, Phillip Grote 1,2, Andreas Kispert 3, Anja Beckers 3, Achim Gossler 3, Martin Werber 1, Bernhard G Herrmann 1,2,a
PMCID: PMC1978083  PMID: 17668009

Abstract

The vertebral column and skeletal muscles of vertebrates are derived from the paraxial mesoderm, which is laid down initially as two stripes of mesenchymal cells alongside the neural tube and subsequently segmented. Previous work has shown that the wingless-type MMTV integration site family (WNT), fibroblast growth factor- and Delta–Notch signalling pathways control presomitic mesoderm (psm) formation and segmentation. Here, we show that the expression of mesogenin 1, a basic helix–loop–helix transcription factor, which is essential for psm maturation, is regulated by synergism between WNT signalling and the T-box 6 transcription factor, involving a feed-forward control mechanism. These findings emphasize the crucial role of WNT signalling in the control of psm formation, maturation and segmentation.

Keywords: WNT signalling, transcriptional regulation, somitogenesis, T-box genes, presomitic mesoderm

Introduction

Paraxial mesoderm, the mesodermal tissue located adjacent to the neural tube, is generated in the primitive streak and tail bud of amniote embryos. On formation, the paraxial mesoderm has a mesenchymal appearance and is called presomitic mesoderm (psm). After maturation, the psm becomes segmented, resulting in two rows of epithelial spheres, the somites, alongside the neural tube. Later in development, the somites undergo further differentiation along the dorsal–ventral axis into dermomyotome and sklerotome, which give rise to dermis and skeletal muscles, and to the axial skeleton, respectively (Gossler & Tam, 2002).

The wingless-type MMTV integration site family (WNT), fibroblast growth factors (FGF), and Delta–Notch signalling cascades control psm formation and segmentation in the trunk and tail of mouse embryos (Aulehla & Herrmann, 2004). The wingless-related MMTV integration site 3A (Wnt3a) gene, FGF receptor 1 (Fgfr1) and the T-box transcription factor brachyury (T) are essential for epithelial–mesenchymal transition, the first stage of psm formation. Mutants lacking any of these factors show an early arrest of trunk elongation at approximately the 8- to 12-somite stage (Wilkinson et al, 1990; Herrmann, 1995; Ciruna et al, 1997; Yoshikawa et al, 1997). T is a target gene of the WNT and FGF signalling cascades, and acts upstream of the T-box 6 transcription factor (Tbx 6; Yamaguchi et al, 1999b; Hofmann et al, 2004). Tbx6 mutants undergo psm formation but fail to maintain cell type identity, resulting in embryos with two additional ectopic neural tubes (Chapman & Papaioannou, 1998).

In addition to the WNT and FGF signalling pathways, the segmentation of the psm involves the Delta–Notch signalling cascade. WNT and Notch signalling are important components of a molecular oscillator, which, in conjunction with the Wnt3a protein and an Fgf8 RNA gradient, determines the position of the segment boundaries (Aulehla et al, 2003; Dubrulle & Pourquie, 2004). Notch signalling is dispensable for segmentation; however, it seems to be essential for the separation of intermingled psm cells belonging to neighbouring segments and for intrasomitic anterior–posterior patterning (Conlon et al, 1995; Hrabe de Angelis et al, 1997; Sato et al, 2002). Recently, we have shown that the expression of Delta-like 1 (Dll1), a crucial activator of Notch gene homologue 1 (Notch1) in the psm, is synergistically controlled by WNT signalling and Tbx6 (Galceran et al, 2004; Hofmann et al, 2004). In addition, Notch signalling in the oscillator is dependent on Wnt3a (Aulehla et al, 2003; Galceran et al, 2004; Hofmann et al, 2004).

Therefore, psm formation, maintenance and segmentation are controlled by a hierarchy of factors including Wnt3a, Fgfr1, T and Tbx6. Wnt3a and Fgfr1 control T expression, whereas T regulates Tbx6. Furthermore, Tbx6 and WNT signalling synergistically control Dll1, the ligand of Notch1, which is essential for somite formation (Hrabe de Angelis et al, 1997; Hofmann et al, 2004). Psm maturation requires the function of mesogenin 1 (Msgn1), a basic helix–loop–helix transcription factor specifically expressed in the psm. Mouse embryos lacking Msgn1 show severely reduced psm and the absence of somites in the trunk (Yoon & Wold, 2000). The transcriptional control of this important factor has not been investigated. Here, we show that Msgn1 is a direct target of WNT signalling and Tbx6, placing Msgn1 downstream of these factors in the hierarchy of regulators controlling paraxial mesoderm development in the mouse.

Results And Discussion

Phenotypic analysis of Msgn1 mutant embryos suggested a role for this gene in the specification and maturation of the paraxial mesoderm downstream of Wnt3a (Yoon & Wold, 2000; Aulehla et al, 2003). To analyse whether Msgn1 expression in the psm depends on Wnt3a function, we used the Wnt3a hypomorphic allele vestigial tail (vt). Homozygous vt embryos are viable but show failure of axial elongation in the tail region, resulting in a vestigial (short) tail phenotype. Psm formation in these mutants is arrested at embryonic day (E) 10.5 in conjunction with an overgrowth of neural tissue (Greco et al, 1996). The levels of Wnt3a messenger RNA are reduced in the tailbud of such embryos at E9.5–E11.5 (Greco et al, 1996). Our expression analysis at E10–E11 (Theiler stage (TS)16–TS18), by in situ hybridization, showed that Msgn1 also is downregulated in these mutants (Fig 1A–L). At E11, residual Msgn1 expression is detected only in a subset of mesodermal cells on the ventral side (Fig 1L), strongly suggesting that Msgn1 is downstream of Wnt3a. Wnt3a directly controls T, which is essential for early mesoderm formation and migration (Wilson & Beddington, 1997; Yamaguchi et al, 1999b; Arnold et al, 2000). Therefore, we analysed Msgn1 expression in T/T embryos at the four- to six-somite stage, just before the arrest of axial elongation in this mutant. Msgn1 expression was completely absent in T/T embryos (Fig 1S,T), suggesting that Msgn1 expression is controlled by T. As T acts upstream of Tbx6 (Hofmann et al, 2004), Tbx6 expression should also depend on Wnt3a. This was confirmed by the significant downregulation of Tbx6 in vt/vt embryos (Fig 1M–R). To relate Msgn1 to Tbx6, we analysed Msgn1 expression in embryos lacking Tbx6 function, using the Tbx6-knockout allele described previously (Chapman & Papaioannou, 1998). Msgn1 expression is strongly downregulated in Tbx6-null mutant embryos, indicating that Tbx6 acts upstream of Msgn1 (Fig 1U,V). Residual expression of Msgn1 in the caudal end of mutant embryos might be due to remaining Wnt3a and T activity in this region. In summary, these data place Msgn1 downstream of Wnt3a, T and Tbx6 in the regulatory network controlling psm formation and maturation.

Figure 1.

Figure 1

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Expression analysis of mutant embryos places mesogenin 1 downstream of Wnt3a, T and Tbx6. RNA transcription was detected by in situ hybridization of wild-type (wt) (A–C,G–I,M–O,S), vt/vt (D–F, J–L, P–R), T−/− (T), Tbx6+/−, (U) and Tbx6−/− (V) embryos. Gene probes are indicated on the left; the position of the sections shown in (C,F,I,L,O,R) are indicated on the image of the corresponding embryo. Staging is according to Theiler (1989); TS16 corresponds to embryonic day (E) 10 and TS18 to E11. Msgn1, mesogenin 1; np, neural plate; nt, neural tube; nt*, ectopic neural tissue; psm, presomitic mesoderm; T, brachyury; Tbx6, T-box 6 transcription factor; vt, vestigial tail; Wnt3a, wingless-related MMTV integration site 3A gene.

Analysis of mutants allowed us to place Msgn1 in the functional hierarchy, but it did not distinguish between direct and indirect control. Therefore, a detailed analysis of the Msgn1 promoter was initiated (Fig 2). First, we mapped the transcriptional start site of Msgn1 55 bp upstream of the translation start, using rapid amplification of 5′ complementary DNA ends (5′-RACE; data not shown). This allowed us to define the promoter region of Msgn1 for which only a single exon is known (ENSEMBL database; Yoon & Wold, 2000). Next, we cloned a genomic fragment covering 7 kb upstream of the translation start and tested its activity in regulating the expression of the lacZ reporter in transgenic embryos. The reporter construct produced strong β-galactosidase activity in the paraxial mesoderm and weaker staining in the lateral plate mesoderm (Fig 2B, b,f,j,n). A search of the −7 kb promoter for putative binding sites for lymphoid enhancer binding factor/transcription factor (Lef/Tcf) regulators, the effectors of WNT signalling and for T-box transcription factors using consensus sequences, identified seven putative binding sites for each type of factor. These binding sites are located in three clusters, two of which are conserved between multiple mammalian species, and partly between mouse and chick (Fig 2A; data not shown; see the supplementary information online). Most of the putative binding sites are located in the cluster extending 1.2 kb upstream of the transcription start. We tested this fragment for promoter activity in transgenic embryos, which showed the same pattern of β-galactosidase activity as transgenic mice carrying the −7 kb promoter, including the ectopic activity in the lateral plate mesoderm (Fig 2B,c,g,k,o). By contrast, transcription of the reporter construct was restricted to the psm and not detected in the lateral mesoderm, as shown by whole-mount in situ hybridization (WISH) analysis using lacZ antisense RNA as a probe (Fig 2B,d,h,l,p). These data suggest that the −1.2 kb promoter of Msgn1 is transiently active in lateral mesoderm progenitor cells in the tailbud, and that the β-galactosidase activity observed in the differentiating lateral mesoderm is due to the high stability of the enzyme. Unlike the wild-type gene, however, reporter gene transcripts were also detected in anterior segmenting psm and in a few somites (Fig 2B,a,e,i,d,h,l). This might be due to either high transcript stability or a lack of timely downregulation of the reporter in psm cells undergoing segmentation. In summary, the −1.2 kb Msgn1 promoter comprises the regulatory elements driving Msgn1 expression in the psm.

Figure 2.

Figure 2

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A 1.2-kb mesogenin 1 promoter fragment is sufficient to drive reporter expression in the presomitic mesoderm. (A) Schematic representation of the reporter constructs analysed in the embryos shown in (B); triangles indicate consensus Lef/Tcf-binding sites and circles indicate T-box-binding sites. The positions of the consensus sites relative to the transcription start site are given below. Asterisks indicate Lef/Tcf-binding sites that are less stringent to the consensus but were integrated in the analysis. (B) Reporter gene (β-galactosidase, LacZ whole-mount in situ hybridization (WISH)) assays of both a 7-kb (b,f,j,n) and a 1.2-kb promoter fragment (c,g,k,o) driving lacZ expression in transgenic embryos show strong β-galactosidase activity in the psm and significant activity in lpm, whereas lacZ transcription is restricted to paraxial mesoderm (d,h,l,p). Msgn1 transcripts are detected only in the psm (a,e,i,m). Hg, hindgut; Lef/Tcf, lymphoid enhancer binding factor/transcription factor; lpm, lateral plate mesoderm; Msgn1, mesogenin 1; np, neural plate; nt, neural tube; psm, presomitic mesoderm; wt, wild type.

The presence of putative Lef/Tcf- and T-box-binding sites in the Msgn1 promoter supported the assumption, based on mutant analysis, that Msgn1 might be a direct target of WNT signalling and/or the T-box transcription factors T and/or Tbx6. To test this assumption, we examined the effect of all three factors on the activity of the Msgn1 promoter in vitro (Fig 3). A construct expressing a constitutively active Lef–β-catenin fusion protein (Lef–bcat; J. Huelsken, unpublished data; see the supplementary information online) was used to assay for WNT activity on the promoter. For T and Tbx6, fusion proteins with the strong transactivation domain of VP16 were used, as the wild-type factors showed only low transactivation activity in the heterologous human embryonic kidney (HEK)293 T cells. Neither factor alone produced strong luciferase reporter activity, although T was the most effective; however, a combination of Tbx6 and Lef–bcat increased the promoter activity more than fivefold above the activity of either single factor. This synergistic activation of the; Msgn1 promoter was specific for Lef–bcat and Tbx6, as T failed to produce this effect (Fig 3B). The strong upregulation of the Msgn1 promoter by Lef–bcat and Tbx6 was prevented by point mutations in the binding sites of either factor, showing that Lef/Tcf- and T-box-binding sites are essential for strong upregulation of Msgn1 expression in vitro (Fig 3B). Furthermore, these results strongly suggested that Msgn1 is controlled by synergistic activity of WNT signalling and Tbx6 in vivo.

Figure 3.

Figure 3

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The mesogenin 1 promoter is synergistically activated by Lef1 and Tbx6 in vitro. (A) Schematic representation of the wild-type (wt) and mutant (mut) reporter constructs used for in vitro (B) and in vivo (see Fig 4) analysis; mutated sites are indicated by crosses. (B) In vitro transactivation assays: transfection of plasmids expressing Tbx6-VP16, T-VP16 or Lef–bcat fusion proteins induce only moderate activation of the wt −1.2-kb Msgn1 promoter, whereas a combination of Tbx6–VP16 and Lef–bcat caused synergistic activation of the reporter, which is prevented by point mutations in either the T-box-binding site (1.2 kb-mut-T) or (three out of four) Lef/Tcf-binding sites (1.2 kb-mut L1,3,4). bcat, β-catenin; Lef, lymphoid enhancer binding factor; Msgn1, mesogenin 1; T, brachyury; Tbx6, T-box 6 transcription factor; Tcf, transcription factor.

To test the role of these factors in Msgn1 expression in the psm, we examined the activity of mutant reporter constructs in mouse embryos. Point mutations in three of the four consensus Lef/Tcf sites located in the −1.2 kb promoter resulted in a strong reduction of the reporter activity in the psm (Fig 4A,a,e,i), leaving residual β-galactosidase activity in the psm and lateral plate mesoderm. Mutation in all four Lef/Tcf sites reduced the reporter activity further in both the psm and the lateral mesoderm (Fig 4A,b,f,j). Mutations in the four consensus T-box sites also strongly affected the reporter activity throughout the paraxial mesoderm (Fig 4A,c,g,k). Residual expression was observed in scattered cells towards the anterior psm. Not even residual reporter activity was detected in the psm with the construct in which both the Lef/Tcf and the T-box sites were mutated (Fig 4A,d,h,l). In summary, the reporter assays in vivo show the essential role of WNT signalling and T-box transcription factors in controlling Msgn1 expression in the psm. These data also support the finding of a synergistic control of Msgn1 by these factors in vivo, as mutations in the binding sites of either factor alone result in strong downregulation of the reporter activity.

Figure 4.

Figure 4

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WNT signalling and Tbx6 synergistically control mesogenin 1 in the presomitic mesoderm. (A) In vivo expression analysis of reporter constructs controlled by the −1.2-kb Msgn1 promoter containing point mutations in Lef/Tcf- and/or T-box consensus binding sites. Expression of all mutant constructs in the psm is downregulated. The β-galactosidase activity in the lateral plate mesoderm is significantly reduced compared with the wild-type construct (see Fig 2), except for the 1.2-kb-mut-T-lacZ reporter (c,g,k). Mutation of all four Lef/Tcf-binding sites nearly abolished β-galactosidase activity in the psm and lateral mesoderm (b,f,j). Expression in the brain is due to positional effects (a). Dashed lines in (e–h) indicate the level of the sections depicted in (i–l). (B) Nuclear material derived from the caudal end of embryonic day (E) 9–E9.5 mouse embryos (caudal to the dashed line) was subjected to chromatin immunoprecipitation (ChIP) assays using Tbx6 or control (IgG) antibodies. The Tbx6 amplicon was specifically enriched with respect to a control amplicon located 6.7 kb downstream of it, strongly suggesting specific binding of Tbx6 protein to the −1.2 kb Msgn1 promoter. Ce, caudal end; da, dorsal aorta; hg, hindgut; Lef/Tcf, lymphoid enhancer binding factor/transcription factor; lpm, lateral plate mesoderm; Msgn1, mesogenin 1; np, neural plate; nt, neural tube; psm, presomitic mesoderm; Tbx6, T-box 6 transcription factor; WNT, wingless-type MMTV integration site family.

In contrast to the constructs containing mutations in the Lef/Tcf-binding sites, the construct carrying mutations in the consensus T-box-binding sites still showed considerable β-galactosidase activity in the lateral plate mesoderm, similar to the wild-type promoter. These data suggest that the transient activation of the reporter in the lateral mesoderm is due to WNT signalling, which is expressed throughout the tailbud.

The reporter assays in vivo, in conjunction with the mutant analyses, strongly suggest that synergistic activity of WNT signalling and Tbx6 control Msgn1 expression in the psm. To test for direct binding of Tbx6 protein to the Msgn1 promoter in vivo, we carried out chromatin immunoprecipitation (ChIP) experiments with chromatin isolated from the caudal region of E9–E9.5 mouse embryos. A genomic fragment containing two of the four T-box-binding sites in the −1.2 kb Msgn1 promoter was found to be strongly overrepresented in amplified DNA from ChIP samples obtained with an antibody against Tbx6, in comparison with a control amplicon located 6.7 kb downstream (Fig 4B). The data show direct binding of Tbx6 to the predicted region of the Msgn1 promoter in vivo.

Lef1 and Tcf7 (previously named Tcf1) have previously been shown to be required for psm formation. Lef1 is a direct target of WNT signalling and shows strong expression in the psm (Galceran et al, 1999, 2004). Combined with our analysis, this suggests that Lef1 and/or Tcf7 might directly bind to the Msgn1 promoter and control Msgn1 expression in the psm.

The detailed analysis of the control of Msgn1 expression in the psm described here considerably improves our understanding of the regulatory network controlling presomitic mesoderm formation, maturation and segmentation (Fig 5). Msgn1 acts downstream of Wnt3a, the only known WNT signal expressed in the tailbud that acts through the canonical pathway. This strongly suggests a direct control of Wnt3a on the activity of Msgn1. The effect of WNT signalling is transient in prospective lateral mesoderm cells, but stabilized in the psm by a double feed-forward mechanism involving the Wnt3a target T and the psm-specific control factor Tbx6, acting downstream of T. The specification, maturation and segmentation of psm seems to be controlled by the synergism between Wnt3a, acting through the effectors Lef1 and Tcf7, and Tbx6, regulating target genes involved in these processes such as Msgn1 and Dll1 (Galceran et al, 2004; Hofmann et al, 2004).

Figure 5.

Figure 5

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Functional hierarchy of factors controlling paraxial mesoderm formation, maturation and segmentation, emphasizing the role of canonical WNT signalling—most probably induced by Wnt3a—as the crucial control factor of these processes. Solid arrows indicate known direct control and dashed arrows, dependence, based on mutant analysis; for details see text. DII1, Delta-like 1; Msgn1, mesogenin 1; psm, presomitic mesoderm; T, brachyury; Tbx6, T-box 6 transcription factor; Wnt3a, wingless-related MMTV integration site 3A gene.

The expression of Notch1 in the psm is dependent on Msgn1 (Yoon & Wold, 2000), and thus indirectly dependent on Wnt3a. Furthermore, Notch signalling in the segmentation clock—an important component of the segmentation mechanism—also indirectly depends on Wnt3a, as shown by downregulation of the Notch1 target Lunatic fringe in vt/vt mutant embryos (Aulehla et al, 2003). Therefore, Wnt3a apparently functions as a crucial control factor for psm formation, maturation and segmentation.

Wnt5a, which signals through the non-canonical WNT pathway, is also expressed in the tailbud and is essential for axial development (Yamaguchi et al, 1999a) future analyses have to address the role of this factor in more detail.

Methods

Expression and reporter constructs. A 7-kb genomic region upstream of the Msgn1 translational start site was obtained by genomic PCR and cloned into a reporter vector containing the lacZ gene and a simian virus 40 polyadenylation sequence. For luciferase reporter constructs, the promoter fragments were inserted into the pGL3-Basic Vector (Promega, Madison, WI, USA). Lef/Tcf- and T/Tbx6-binding sites were modified using the QuikChange Multi Site-Directed Mutagenesis Kit (Stratagene, La Jolla, CA, USA). The transcriptional start site of Msgn1 was determined by 5′-RACE PCR (Invitrogen, Carlsbad, CA, USA).

DNA microinjection and staining for β-galactosidase activity. LacZ reporter constructs were analysed in transient transgenic embryos produced by pronuclear injection of fertilized mouse eggs, followed by β-galactosidase activity assays as described previously (Beckers et al, 2000). The numbers of embryos analysed at E9.5–E10.5 for lacZ transcription or β-galactosidase activity are given in the supplementary information online.

In situ hybridization and histology. WISH analyses and the preparation of histological sections were carried out using standard procedures.

Cell culture and reporter gene assays. Reporter gene assays in vitro were carried out in HEK293 T cells according to standard procedures (for details, see the supplementary information online).

Chromatin immunoprecipitation. ChIP assays were carried out using tailbud tissue derived from 80 to 100 dissected E9–E9.5 mouse embryos essentially according to the Abcam (Cambridge, UK) ChIP protocol (Abcam), with minor modifications (for details, see the supplementary information online).

Supplementary information is available at EMBO reports online (http://www.nature.com/embor/journal/v8/n8/extref/7401030-s1.pdf).

Supplementary Material

Supplementary Information

7401030-s1.pdf (170.7KB, pdf)

Acknowledgments

We thank M. Scholze and A. König for excellent technical assistance, T. Matkovic for in situ hybridization of Tbx6 mutant embryos, J. Huelsken for the Lef–bcat construct, J.K. Yoon for the Msgn1 probe, D. Chapman for Tbx6 antibodies, and V. Papaioannou for the Tbx6-knockout mouse line. This work was supported by the German Federal Ministry for Education and Research as part of the National Genome Research Network. We are responsible for the content of this publication.

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Supplementary Materials

Supplementary Information

7401030-s1.pdf (170.7KB, pdf)

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