Document Detail

Differential RET signaling pathways drive development of the enteric lymphoid and nervous systems.
MedLine Citation:
PMID:  22855506     Owner:  NLM     Status:  MEDLINE    
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.
Amisha Patel; Nicola Harker; Lara Moreira-Santos; Manuela Ferreira; Kieran Alden; Jon Timmis; Katie Foster; Anna Garefalaki; Panayotis Pachnis; Paul Andrews; Hideki Enomoto; Jeffrey Milbrandt; Vassilis Pachnis; Mark C Coles; Dimitris Kioussis; Henrique Veiga-Fernandes
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Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2012-07-31
Journal Detail:
Title:  Science signaling     Volume:  5     ISSN:  1937-9145     ISO Abbreviation:  Sci Signal     Publication Date:  2012  
Date Detail:
Created Date:  2012-08-02     Completed Date:  2012-12-06     Revised Date:  2014-02-20    
Medline Journal Info:
Nlm Unique ID:  101465400     Medline TA:  Sci Signal     Country:  United States    
Other Details:
Languages:  eng     Pagination:  ra55     Citation Subset:  IM    
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MeSH Terms
Blotting, Western
Cells, Cultured
Enteric Nervous System / embryology*
Gastrointestinal Tract / embryology*,  innervation
Gene Expression Regulation, Developmental / physiology
Glial Cell Line-Derived Neurotrophic Factor Receptors / metabolism*
Microscopy, Confocal
Morphogenesis / physiology*
Peyer's Patches / embryology*
Proto-Oncogene Proteins c-ret / metabolism*
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / physiology*
Grant Support
G0601156//Medical Research Council; G0800973//Medical Research Council; MC_U117537087//Medical Research Council; U117512796//Medical Research Council
Reg. No./Substance:
0/Glial Cell Line-Derived Neurotrophic Factor Receptors; EC Proteins c-ret; EC protein, mouse

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