Letter | Published:

Tyrosine kinase receptor RET is a key regulator of Peyer’s Patch organogenesis

Nature volume 446, pages 547551 (29 March 2007) | Download Citation



Normal organogenesis requires co-ordinate development and interaction of multiple cell types, and is seemingly governed by tissue specific factors. Lymphoid organogenesis during embryonic life is dependent on molecules the temporal expression of which is tightly regulated. During this process, haematopoietic ‘inducer’ cells interact with stromal ‘organizer’ cells, giving rise to the lymphoid organ primordia1. Here we show that the haematopoietic cells in the gut exhibit a random pattern of motility before aggregation into the primordia of Peyer’s patches, a major component of the gut-associated lymphoid tissue. We further show that a CD45+CD4-CD3-Il7Rα-c-Kit+CD11c+ haematopoietic population expressing lymphotoxin has an important role in the formation of Peyer’s patches. A subset of these cells expresses the receptor tyrosine kinase RET, which is essential for mammalian enteric nervous system formation2. We demonstrate that RET signalling is also crucial for Peyer’s patch formation. Functional genetic analysis revealed that Gfra3-deficiency results in impairment of Peyer’s patch development, suggesting that the signalling axis RET/GFRα3/ARTN is involved in this process. To support this hypothesis, we show that the RET ligand ARTN is a strong attractant of gut haematopoietic cells, inducing the formation of ectopic Peyer’s patch-like structures. Our work strongly suggests that the RET signalling pathway, by regulating the development of both the nervous and lymphoid system in the gut, has a key role in the molecular mechanisms that orchestrate intestine organogenesis.

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The work described in this paper was funded by the Medical Research Council (MRC), UK. We thank C. Atkins and G. Preece for cell sorting; S. Pagakis, M. Tolaini, T. Norton and K. Williams for technical assistance. We also thank H. Hamada and J. Nishino for the GFRα3 knockout mice. H.V.-F. and K.E.F. were supported by a grant from the European Union.

Author information


  1. Division of Molecular Immunology,

    • Henrique Veiga-Fernandes
    • , Mark C. Coles
    • , Katie E. Foster
    • , Amisha Patel
    • , Adam Williams
    •  & Dimitris Kioussis
  2. Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK

    • Dipa Natarajan
    • , Amanda Barlow
    •  & Vassilis Pachnis


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Reprints and permissions information is available at www.nature.com/reprints. The authors declare no competing financial interests.

Corresponding author

Correspondence to Dimitris Kioussis.

Supplementary information

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  1. 1.

    Supplementary Information

    This file contains Supplementary Figures1-6, Supplementary Methods 1-2 and Supplementary Movie Legends 1-3.


  1. 1.

    Supplementary Movie 1

    This file contains Supplementary Movie 1. This movie shows a time lapse sequence of E15.5 intestines. GFP+cells exhibit a remarkable, seemingly random motility, sometimes reaching 6µm/min. Time lapse images were taken for 25 minutes.

  2. 2.

    Supplementary Movie 2

    This file contains Supplementary Movie 2. This movie shows a high magnification of the cell migration on the wall of the embryonic intestine E15.5, allowing precise cell tracking measurements (Fig.2b). Time lapse images were taken for 25 minutes.

  3. 3.

    Supplementary Movie 3

    This file contains Supplementary Movie 3. This movie shows that the PP primordiumis comprised of different subsets of haematopoietic cells, here represented in green (GFP+) and yellow (GFP+CD4+).

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