Abstract
Instructive programmes guiding cell-fate decisions in the developing mouse embryo are controlled by a few so-termed master regulators. Genetic studies demonstrate that the T-box transcription factor Eomesodermin (Eomes) is essential for epithelial-to-mesenchymal transition, mesoderm migration and specification of definitive endoderm during gastrulation1. Here we report that Eomes expression within the primitive streak marks the earliest cardiac mesoderm and promotes formation of cardiovascular progenitors by directly activating the bHLH (basic-helix-loop-helix) transcription factor gene Mesp1 upstream of the core cardiac transcriptional machinery2,3,4. In marked contrast to Eomes/Nodal signalling interactions that cooperatively regulate anterior–posterior axis patterning and allocation of the definitive endoderm cell lineage1,5,6,7,8, formation of cardiac progenitors requires only low levels of Nodal activity accomplished through a Foxh1/Smad4-independent mechanism. Collectively, our experiments demonstrate that Eomes governs discrete context-dependent transcriptional programmes that sequentially specify cardiac and definitive endoderm progenitors during gastrulation.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Rent or buy this article
Prices vary by article type
from$1.95
to$39.95
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
References
Arnold, S. J., Hofmann, U. K., Bikoff, E. K. & Robertson, E. J. Pivotal roles for eomesodermin during axis formation, epithelium-to-mesenchyme transition and endoderm specification in the mouse. Development 135, 501–511 (2008).
Bondue, A. et al. Mesp1 acts as a master regulator of multipotent cardiovascular progenitor specification. Cell Stem Cell 3, 69–84 (2008).
David, R. et al. MesP1 drives vertebrate cardiovascular differentiation through Dkk-1-mediated blockade of Wnt-signalling. Nat. Cell Biol. 10, 338–345 (2008).
Lindsley, R. C. et al. Mesp1 coordinately regulates cardiovascular fate restriction and epithelial–mesenchymal transition in differentiating ESCs. Cell Stem Cell 3, 55–68 (2008).
Vincent, S. D., Dunn, N. R., Hayashi, S., Norris, D. P. & Robertson, E. J. Cell fate decisions within the mouse organizer are governed by graded Nodal signals. Genes Dev. 17, 1646–1662 (2003).
Chu, G. C., Dunn, N. R., Anderson, D. C., Oxburgh, L. & Robertson, E. J. Differential requirements for Smad4 in TGFβ-dependent patterning of the early mouse embryo. Development 131, 3501–3512 (2004).
Dunn, N. R., Vincent, S. D., Oxburgh, L., Robertson, E. J. & Bikoff, E. K. Combinatorial activities of Smad2 and Smad3 regulate mesoderm formation and patterning in the mouse embryo. Development 131, 1717–1728 (2004).
Ben-Haim, N. et al. The nodal precursor acting via activin receptors induces mesoderm by maintaining a source of its convertases and BMP4. Dev. Cell 11, 313–323 (2006).
Arnold, S. J. & Robertson, E. J. Making a commitment: cell lineage allocation and axis patterning in the early mouse embryo. Nat. Rev. Mol. Cell Biol. 10, 91–103 (2009).
Lawson, K. A., Meneses, J. J. & Pedersen, R. A. Clonal analysis of epiblast fate during germ layer formation in the mouse embryo. Development 113, 891–911 (1991).
Tam, P. P., Parameswaran, M., Kinder, S. J. & Weinberger, R. P. The allocation of epiblast cells to the embryonic heart and other mesodermal lineages: the role of ingression and tissue movement during gastrulation. Development 124, 1631–1642 (1997).
Hoodless, P. A. et al. FoxH1 (Fast) functions to specify the anterior primitive streak in the mouse. Genes Dev. 15, 1257–1271 (2001).
Yamamoto, M. et al. The transcription factor FoxH1 (FAST) mediates Nodal signaling during anterior–posterior patterning and node formation in the mouse. Genes Dev. 15, 1242–1256 (2001).
Russ, A. P. et al. Eomesodermin is required for mouse trophoblast development and mesoderm formation. Nature 404, 95–99 (2000).
Ciruna, B. G. & Rossant, J. Expression of the T-box gene Eomesodermin during early mouse development. Mech. Dev. 81, 199–203 (1999).
Soriano, P. Generalized lacZ expression with the ROSA26 Cre reporter strain. Nat. Genet. 21, 70–71 (1999).
Friedrich, G. & Soriano, P. Promoter traps in embryonic stem cells: a genetic screen to identify and mutate developmental genes in mice. Genes Dev. 5, 1513–1523 (1991).
Arnold, S. J., Sugnaseelan, J., Groszer, M., Srinivas, S. & Robertson, E. J. Generation and analysis of a mouse line harboring GFP in the Eomes/Tbr2 locus. Genesis 47, 775–781 (2009).
Tremblay, K. D., Hoodless, P. A., Bikoff, E. K. & Robertson, E. J. Formation of the definitive endoderm in mouse is a Smad2-dependent process. Development 127, 3079–3090 (2000).
Kuzmenkin, A. et al. Functional characterization of cardiomyocytes derived from murine induced pluripotent stem cells in vitro. FASEB J. 23, 4168–4180 (2009).
Saga, Y. Genetic rescue of segmentation defect in MesP2-deficient mice by MesP1 gene replacement. Mech. Dev. 75, 53–66 (1998).
Saga, Y. et al. MesP1 is expressed in the heart precursor cells and required for the formation of a single heart tube. Development 126, 3437–3447 (1999).
Kitajima, S., Takagi, A., Inoue, T. & Saga, Y. MesP1 and MesP2 are essential for the development of cardiac mesoderm. Development 127, 3215–3226 (2000).
Saga, Y., Hata, N., Koseki, H. & Taketo, M. M. Mesp2: a novel mouse gene expressed in the presegmented mesoderm and essential for segmentation initiation. Genes Dev. 11, 1827–1839 (1997).
Haraguchi, S. et al. Transcriptional regulation of Mesp1 and Mesp2 genes:differential usage of enhancers during development. Mech. Dev. 108, 59–69 (2001).
Oginuma, M., Hirata, T. & Saga, Y. Identification of presomitic mesoderm (PSM)-specific Mesp1 enhancer and generation of a PSM-specific Mesp1/Mesp2-null mouse using BAC-based rescue technology. Mech. Dev. 125, 432–440 (2008).
Yasuhiko, Y. et al. Functional importance of evolutionally conserved Tbx6 binding sites in the presomitic mesoderm-specific enhancer of Mesp2. Development 135, 3511–3519 (2008).
Habara-Ohkubo, A. Differentiation of beating cardiac muscle cells from a derivative of P19 embryonal carcinoma cells. Cell Struct. Funct. 21, 101–110 (1996).
Chapman, D. L. et al. Expression of the T-box family genes, Tbx1–Tbx5, during early mouse development. Dev. Dyn. 206, 379–390 (1996).
Chapman, D. L., Agulnik, I., Hancock, S., Silver, L. M. & Papaioannou, V. E. Tbx6, a mouse T-Box gene implicated in paraxial mesoderm formation at gastrulation. Dev. Biol. 180, 534–542 (1996).
Wilkinson, D. G., Bhatt, S. & Herrmann, B. G. Expression pattern of the mouse T gene and its role in mesoderm formation. Nature 343, 657–659 (1990).
Shawlot, W. & Behringer, R. R. Requirement for Lim1 in head-organizer function. Nature 374, 425–430 (1995).
Tam, P. P., Khoo, P. L., Wong, N., Tsang, T. E. & Behringer, R. R. Regionalization of cell fates and cell movement in the endoderm of the mouse gastrula and the impact of loss of Lhx1(Lim1) function. Dev. Biol. 274, 171–187 (2004).
Norris, D. P., Brennan, J., Bikoff, E. K. & Robertson, E. J. The Foxh1-dependent autoregulatory enhancer controls the level of Nodal signals in the mouse embryo. Development 129, 3455–3468 (2002).
Teo, A. K. et al. Pluripotency factors regulate definitive endoderm specification through eomesodermin. Genes Dev. 25, 238–250 (2011).
Powers, S. E. et al. Tgif1 and Tgif2 regulate Nodal signaling and are required for gastrulation. Development 137, 249–259 (2010).
Nagy, A., Gertsenstein, M., Vintersten, K. & Behringer, R. Manipulating the mouse embryo: a laboratory manual 3rd edn (Cold Spring Harbor Laboratory Press, 2003).
Niwa, H. et al. Interaction between Oct3/4 and Cdx2 determines trophectoderm differentiation. Cell 123, 917–929 (2005).
Costello, I., Biondi, C. A., Taylor, J. M., Bikoff, E. K. & Robertson, E. J. Smad4-dependent pathways control basement membrane deposition and endodermal cell migration at early stages of mouse development. BMC Dev. Biol. 9, 54 (2009).
Acknowledgements
We thank N. Hortin, A. Salman and M. Pavlovic for technical assistance, C. Böhlke and A. Hofherr for help with imaging techniques, S. Stefanovic for qPCR primer optimization and H. Niwa and Y. Saga for plasmids. This work was supported by the Emmy Noether Programme and SFB850 of the German Research Council to S.J.A. and a Programme Grant from the Wellcome Trust to E.J.R.
Author information
Authors and Affiliations
Contributions
I.C., E.K.B., E.J.R. and S.J.A. designed experiments, I.C., I-M.P., S.D., E.J.R. and S.J.A. carried out research, I.C., E.J.R. and S.J.A. analysed data and I.C., E.K.B., E.J.R. and S.J.A. wrote and edited the manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Information
Supplementary Information (PDF 1698 kb)
Supplementary Movie 1
Supplementary Information (MOV 488 kb)
Supplementary Movie 2
Supplementary Information (MOV 989 kb)
Rights and permissions
About this article
Cite this article
Costello, I., Pimeisl, IM., Dräger, S. et al. The T-box transcription factor Eomesodermin acts upstream of Mesp1 to specify cardiac mesoderm during mouse gastrulation. Nat Cell Biol 13, 1084–1091 (2011). https://doi.org/10.1038/ncb2304
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ncb2304
This article is cited by
-
The T-box transcription factor Eomesodermin governs haemogenic competence of yolk sac mesodermal progenitors
Nature Cell Biology (2021)
-
Understanding Heart Field Progenitor Cells for Modeling Congenital Heart Diseases
Current Cardiology Reports (2021)
-
Vertebrate cranial mesoderm: developmental trajectory and evolutionary origin
Cellular and Molecular Life Sciences (2020)
-
Eomes and Brachyury control pluripotency exit and germ-layer segregation by changing the chromatin state
Nature Cell Biology (2019)
-
A conserved regulatory program initiates lateral plate mesoderm emergence across chordates
Nature Communications (2019)