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Sci. Signal., 31 July 2012
Vol. 5, Issue 235, p. ra55
[DOI: 10.1126/scisignal.2002734]


Differential RET Signaling Pathways Drive Development of the Enteric Lymphoid and Nervous Systems

Amisha Patel1*, Nicola Harker1*, Lara Moreira-Santos2*, Manuela Ferreira2, Kieran Alden3,4, Jon Timmis4, Katie Foster1, Anna Garefalaki1, Panayotis Pachnis1, Paul Andrews4, Hideki Enomoto5, Jeffrey Milbrandt6, Vassilis Pachnis7, Mark C. Coles3, Dimitris Kioussis1, and Henrique Veiga-Fernandes2{dagger}

1 Division of Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
2 Instituto de Medicina Molecular, Faculdade de Medicina de Lisboa, Av. Prof. Egas Moniz, Edifício Egas Moniz, 1649-028 Lisboa, Portugal.
3 Centre for Immunology and Infection, Department of Biology and Hull York Medical School, University of York, York YO10 5DD, UK.
4 Departments of Computer Science and Electronics, University of York, York YO10 5DD, UK.
5 Laboratory for Neuronal Differentiation and Regeneration, RIKEN Center for Developmental Biology, Kobe 650-0047, Japan.
6 Hope Centre for Neurological Disorders, Genetics Department, Washington University School of Medicine, St. Louis, MO 63110, USA.
7 Division of Molecular Neurobiology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.

* These authors contributed equally to this work.

Abstract: During the early development of the gastrointestinal tract, signaling through the receptor tyrosine kinase RET is required for initiation of lymphoid organ (Peyer’s patch) formation and for intestinal innervation by enteric neurons. RET signaling occurs through glial cell line–derived neurotrophic factor (GDNF) family receptor α co-receptors present in the same cell (signaling in cis). It is unclear whether RET signaling in trans, which occurs in vitro through co-receptors from other cells, has a biological role. We showed that the initial aggregation of hematopoietic cells to form lymphoid clusters occurred in a RET-dependent, chemokine-independent manner through adhesion-mediated arrest of lymphoid tissue initiator (LTin) cells. Lymphoid tissue inducer cells were not necessary for this initiation phase. LTin cells responded to all RET ligands in trans, requiring factors from other cells, whereas RET was activated in enteric neurons exclusively by GDNF in cis. Furthermore, genetic and molecular approaches revealed that the versatile RET responses in LTin cells were determined by distinct patterns of expression of the genes encoding RET and its co-receptors. Our study shows that a trans RET response in LTin cells determines the initial phase of enteric lymphoid organ morphogenesis, and suggests that differential co-expression of Ret and Gfra can control the specificity of RET signaling.

{dagger} To whom correspondence should be addressed. E-mail: jhfernandes{at}

Citation: A. Patel, N. Harker, L. Moreira-Santos, M. Ferreira, K. Alden, J. Timmis, K. Foster, A. Garefalaki, P. Pachnis, P. Andrews, H. Enomoto, J. Milbrandt, V. Pachnis, M. C. Coles, D. Kioussis, H. Veiga-Fernandes, Differential RET Signaling Pathways Drive Development of the Enteric Lymphoid and Nervous Systems. Sci. Signal. 5, ra55 (2012).

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