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Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells

Nature volume 470, pages 394–398 (2011)Cite this article

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Abstract

The classical view of neural plate development held that it arises from the ectoderm, after its separation from the mesodermal and endodermal lineages. However, recent cell-lineage-tracing experiments indicate that the caudal neural plate and paraxial mesoderm are generated from common bipotential axial stem cells originating from the caudal lateral epiblast1,2. Tbx6 null mutant mouse embryos which produce ectopic neural tubes at the expense of paraxial mesoderm3 must provide a clue to the regulatory mechanism underlying this neural versus mesodermal fate choice. Here we demonstrate that Tbx6-dependent regulation of Sox2 determines the fate of axial stem cells. In wild-type embryos, enhancer N1 of the neural primordial gene Sox2 is activated in the caudal lateral epiblast, and the cells staying in the superficial layer sustain N1 activity and activate Sox2 expression in the neural plate4,5,6. In contrast, the cells destined to become mesoderm activate Tbx6 and turn off enhancer N1 before migrating into the paraxial mesoderm compartment. In Tbx6 mutant embryos, however, enhancer N1 activity persists in the paraxial mesoderm compartment, eliciting ectopic Sox2 activation and transforming the paraxial mesoderm into neural tubes. An enhancer-N1-specific deletion mutation introduced into Tbx6 mutant embryos prevented this Sox2 activation in the mesodermal compartment and subsequent development of ectopic neural tubes, indicating that Tbx6 regulates Sox2 via enhancer N1. Tbx6-dependent repression of Wnt3a in the paraxial mesodermal compartment is implicated in this regulatory process. Paraxial mesoderm-specific misexpression of a Sox2 transgene in wild-type embryos resulted in ectopic neural tube development. Thus, Tbx6 represses Sox2 by inactivating enhancer N1 to inhibit neural development, and this is an essential step for the specification of paraxial mesoderm from the axial stem cells.

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Figure 1: Enhancer N1 of the mouse Sox2 gene and its activity in comparison with Sox2 and Tbx6 expression.
Figure 2: Ectopic activation of enhancer N1, Sox2 expression and neural development in the paraxial mesoderm compartment of Tbx6 −/− embryos.
Figure 3: Enhancer-N1-dependent paraxial Sox2 expression and ectopic neural tube development in Tbx6 −/− embryos, and their suppression in Tbx6 −/−  ΔN1/ΔN1 double mutants.
Figure 4: Development of ectopic neural tubes from the wild-type paraxial mesoderm by misexpression of exogenous Sox2.

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Acknowledgements

We thank the members of Kondoh laboratory for discussions. This study was supported by Grants-in-Aid for Scientific Research from MEXT Japan to T.T. and H.K., an NIH grant to V.E.P., and MRC funding to R.L.-B.

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Authors and Affiliations

  1. Graduate School of Frontier Biosciences, Osaka University, 1-3 Yamadaoka, Suita, Osaka 565-0871, Japan ,

    Tatsuya Takemoto, Masanori Uchikawa, Megumi Yoshida & Hisato Kondoh

  2. Division of Stem Cell Biology and Developmental Genetics, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK,

    Donald M. Bell & Robin Lovell-Badge

  3. Department of Genetics and Development, College of Physicians and Surgeons of Columbia University, 701 West 168th Street, New York, New York 10032, USA,

    Virginia E. Papaioannou

Authors
  1. Tatsuya Takemoto
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Contributions

T.T. and H.K. conceived the project; T.T. carried out major experiments; T.T. and H.K. analysed data; M.U. and M.Y. aided production and analysis of enhancer N1 mutant mice; V.E.P. provided Tbx6 mutant mice; D.M.B., R.L.-B. and V.E.P. first indicated Sox2 disregulation in the Tbx6 mutant mice; and T.T. and H.K. wrote the manuscript.

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Correspondence to Hisato Kondoh.

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The authors declare no competing financial interests.

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Takemoto, T., Uchikawa, M., Yoshida, M. et al. Tbx6-dependent Sox2 regulation determines neural or mesodermal fate in axial stem cells. Nature 470, 394–398 (2011). https://doi.org/10.1038/nature09729

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