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Induction of the mammalian node requires Arkadia function in the extraembryonic lineages

Nature volume 410, pages 825–830 (2001)Cite this article

Abstract

The early mammalian embryo is patterned by signals emanating from extraembryonic and embryonic signalling centres, most notably the anterior visceral endoderm (AVE) and the node, respectively1. The AVE is responsible for anterior development, whereas further axis specification depends on the node, the equivalent of Spemann's organizer2,3. Formation of the node, at the anterior primitive streak, depends on expression of the transcription factor HNF3β (ref. 4). However, both the source and the nature of the signals responsible for inducing the node have been unknown. Here we describe a recessive lethal mutation, arkadia, generated using gene-trap mutagenesis. Mutant embryos establish an AVE but fail to maintain anterior embryonic structures and lack a node. The mutation has disrupted the Arkadia gene, which encodes a putative intracellular protein containing a RING domain. Arkadia is essential for HNF3β expression in the anterior primitive streak. Analysis with chimaeras, however, shows that Arkadia functions within extraembryonic tissues, revealing that these are required to induce the node. Furthermore, our experiments show that Arkadia interacts genetically with the transforming growth factor (TGF)β-like factor Nodal5,6,7, implying that Nodal mediates the function of Arkadia in node induction.

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Figure 1: Neurectoderm development in arkadia embryos.
Figure 2: Mesendoderm and definitive endodem in arkadia embryos.
Figure 3: Molecular analysis of Arkadia.
Figure 4: Anterior primitive streak (APS) defects in arkadia embryos.
Figure 5: Arkadia function in the extraembryonic lineages.

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Acknowledgements

Gene trap mutagenesis was done in the laboratory of E. J. Robertson at Columbia University, New York. We thank R. Lovell-Badge, T. Jessell, E. Robertson and A. Streit for reading the manuscript; E. L. Ferguson for discussions; E. Robertson for the gift of the GT-carrier and nodal (+/-) mice and T. Rodriguez for rederivation of the latter; P. Soriano for the Rosa βgeo vector and virus-producing cell lines; S.-L. Ang, R. Beddington, E. De Robertis, P. Gruss, T. Jessell and J. Rossant for WISH probes; M. Alexiou, H. Wood and S. Malas for advice and support; and A. Simpkins, R. Grahame, G. Baker and E. Damien for technical support.

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Author notes

  1. Ruth Arkell & James J. Walsh

    Present address: Mammalian Genetics Unit, MRC, Harwell, OX11 ORD, UK

  2. Daniel Swan

    Present address: Centre for Genome Research, The University of Edinburgh, Edinburgh, EH9 3JQ, UK

  3. Ruth Arkell and Daniel Swan: These authors contributed equally to this work.

Authors and Affiliations

  1. Mammalian Neurogenesis, MRC Clinical Sciences Centre, Imperial College School of Medicine, Hammersmith Hospital, Du Cane Road, London, W12 0NN, UK

    Vasso Episkopou, Ruth Arkell, Paula M. Timmons, James J. Walsh, Rebecca L. Andrew & Daniel Swan

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  1. Vasso Episkopou
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Correspondence to Vasso Episkopou.

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Episkopou, V., Arkell, R., Timmons, P. et al. Induction of the mammalian node requires Arkadia function in the extraembryonic lineages. Nature 410, 825–830 (2001). https://doi.org/10.1038/35071095

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