Tyrosine kinase receptor RET is a key regulator of Peyer's patch organogenesis.
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 primordia. 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-Il7Ralpha-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 formation. 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/GFRalpha3/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.
Veiga-Fernandes
Henrique
H
Division of Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
Coles
Mark C
MC
Foster
Katie E
KE
Patel
Amisha
A
Williams
Adam
A
Natarajan
Dipa
D
Barlow
Amanda
A
Pachnis
Vassilis
V
Kioussis
Dimitris
D
D000818:Animals; D018801:CD2 Antigens / Q000235:genetics / Q000378:metabolism; D002465:Cell Movement; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism; D006410:Hematopoiesis; D006801:Humans; D007422:Intestines / Q000166:cytology / Q000196:embryology / Q000201:enzymology / Q000276:immunology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation / Q000235:genetics; D009419:Nerve Tissue Proteins / Q000378:metabolism; D038081:Organogenesis; D010581:Peyer's Patches / Q000166:cytology / Q000196:embryology* / Q000201:enzymology*; D051096:Proto-Oncogene Proteins c-ret / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction
C116599:Artn protein, mouse; D018801:CD2 Antigens; C494994:Gfra3 protein, mouse; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D009419:Nerve Tissue Proteins; D051096:Proto-Oncogene Proteins c-ret