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

Nature volume 446, pages 547–551 (2007)Cite this article

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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Figure 1: Colonization of the embryonic intestine by GFP + haematopoietic cells.
Figure 2: Phenotype of embryonic GFP + haematopoietic cells in the intestine.
Figure 3: Peyer’s patch development in tyrosine kinase RET mutants.
Figure 4: RET/GFRα3/ARTN signalling axis and Peyer’s patch development.

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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.

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Authors and 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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  1. Henrique Veiga-Fernandes
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Correspondence to Dimitris Kioussis.

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Supplementary information

Supplementary Information

This file contains Supplementary Figures1-6, Supplementary Methods 1-2 and Supplementary Movie Legends 1-3. (PDF 2221 kb)

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. (MOV 4209 kb)

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. (MOV 504 kb)

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+). (MOV 9684 kb)

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Veiga-Fernandes, H., Coles, M., Foster, K. et al. Tyrosine kinase receptor RET is a key regulator of Peyer’s Patch organogenesis. Nature 446, 547–551 (2007). https://doi.org/10.1038/nature05597

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