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

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Abstract

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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References

  1. 1.

    Organogenesis of lymphoid tissues. Nature Rev. Immunol. 3, 292–303 (2003)

  2. 2.

    , , , & Defects in the kidney and enteric nervous system of mice lacking the tyrosine kinase receptor Ret. Nature 367, 380–383 (1994)

  3. 3.

    , , & Three distinctive steps in Peyer's patch formation of murine embryo. Int. Immunol. 9, 507–514 (1997)

  4. 4.

    et al. Essential role of IL-7 receptor alpha in the formation of Peyer's patch anlage. Int. Immunol. 10, 1–6 (1998)

  5. 5.

    et al. IL-7 receptor α+ CD3- cells in the embryonic intestine induces the organizing center of Peyer's patches. Int. Immunol. 11, 643–655 (1999)

  6. 6.

    et al. Selective defects in the development of the fetal and adult lymphoid system in mice with an Ikaros null mutation. Immunity 5, 537–549 (1996)

  7. 7.

    et al. Retinoid-related orphan receptor γ (RORγ) is essential for lymphoid organogenesis and controls apoptosis during thymopoiesis. Proc. Natl Acad. Sci. USA 97, 10132–10137 (2000)

  8. 8.

    et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix–loop–helix inhibitor Id2. Nature 397, 702–706 (1999)

  9. 9.

    et al. Regulation of peripheral lymph node genesis by the tumor necrosis factor family member TRANCE. J. Exp. Med. 192, 1467–1478 (2000)

  10. 10.

    et al. OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymph-node organogenesis. Nature 397, 315–323 (1999)

  11. 11.

    et al. RANK is essential for osteoclast and lymph node development. Genes Dev. 13, 2412–2424 (1999)

  12. 12.

    et al. A putative chemokine receptor, BLR1, directs B cell migration to defined lymphoid organs and specific anatomic compartments of the spleen. Cell 87, 1037–1047 (1996)

  13. 13.

    et al. A chemokine-driven positive feedback loop organizes lymphoid follicles. Nature 406, 309–314 (2000)

  14. 14.

    et al. Lymphotoxin-α-deficient mice. Effects on secondary lymphoid organ development and humoral immune responsiveness. J. Immunol. 155, 1685–1693 (1995)

  15. 15.

    et al. Abnormal development of peripheral lymphoid organs in mice deficient in lymphotoxin. Science 264, 703–707 (1994)

  16. 16.

    , , , & The lymphotoxin β receptor controls organogenesis and affinity maturation in peripheral lymphoid tissues. Immunity 9, 59–70 (1998)

  17. 17.

    et al. Distinct roles in lymphoid organogenesis for lymphotoxins α and β revealed in lymphotoxin β-deficient mice. Immunity 6, 491–500 (1997)

  18. 18.

    et al. Developmental defects of lymphoid cells in Jak3 kinase-deficient mice. Immunity 3, 771–782 (1995)

  19. 19.

    et al. Defective lymphoid development in mice lacking expression of the common cytokine receptor gamma chain. Immunity 2, 223–238 (1995)

  20. 20.

    et al. Role of T and NK cells and IL7/IL7r interactions during neonatal maturation of lymph nodes. Proc. Natl Acad. Sci. USA 103, 13457–13462 (2006)

  21. 21.

    et al. Compartmentalization of Peyer's patch anlagen before lymphocyte entry. J. Immunol. 166, 3702–3709 (2001)

  22. 22.

    , , , & Surface lymphotoxin α/β complex is required for the development of peripheral lymphoid organs. J. Exp. Med. 184, 1999–2006 (1996)

  23. 23.

    et al. Abnormal development of secondary lymphoid tissues in lymphotoxin β-deficient mice. Proc. Natl Acad. Sci. USA 94, 9302–9307 (1997)

  24. 24.

    et al. In vivo depletion of CD11c+ dendritic cells abrogates priming of CD8+ T cells by exogenous cell-associated antigens. Immunity 17, 211–220 (2002)

  25. 25.

    et al. Differential activities of the RET tyrosine kinase receptor isoforms during mammalian embryogenesis. Genes Dev. 15, 2433–2444 (2001)

  26. 26.

    et al. Defects in enteric innervation and kidney development in mice lacking GDNF. Nature 382, 73–76 (1996)

  27. 27.

    et al. Renal and neuronal abnormalities in mice lacking GDNF. Nature 382, 76–79 (1996)

  28. 28.

    et al. GFRα1 is an essential receptor component for GDNF in the developing nervous system and kidney. Neuron 21, 53–62 (1998)

  29. 29.

    et al. Artemin is a vascular-derived neurotropic factor for developing sympathetic neurons. Neuron 35, 267–282 (2002)

  30. 30.

    et al. Expression and function of glial cell line-derived neurotrophic factor family ligands and their receptors on human immune cells. J. Immunol. 175, 2301–2308 (2005)

  31. 31.

    et al. Transgenic mice with hematopoietic and lymphoid specific expression of Cre. Eur. J. Immunol. 33, 314–325 (2003)

  32. 32.

    et al. GFR α3, a component of the artemin receptor, is required for migration and survival of the superior cervical ganglion. Neuron 23, 725–736 (1999)

  33. 33.

    , , & Quantification of multiple gene expression in individual cells. Genome Res. 14, 1938–1947 (2004)

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Acknowledgements

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

Affiliations

  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

PDF files

  1. 1.

    Supplementary Information

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

Videos

  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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DOI

https://doi.org/10.1038/nature05597

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