title: Differential RET signaling pathways drive development of the enteric lymphoid and nervous systems.
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.
authors.affiliation: Division of Molecular Immunology, MRC National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK.
authors.forename: Amisha
authors.initials: A
authors.lastname: Patel
authors.forename: Nicola
authors.initials: N
authors.lastname: Harker
authors.forename: Lara
authors.initials: L
authors.lastname: Moreira-Santos
authors.forename: Manuela
authors.initials: M
authors.lastname: Ferreira
authors.forename: Kieran
authors.initials: K
authors.lastname: Alden
authors.forename: Jon
authors.initials: J
authors.lastname: Timmis
authors.forename: Katie
authors.initials: K
authors.lastname: Foster
authors.forename: Anna
authors.initials: A
authors.lastname: Garefalaki
authors.forename: Panayotis
authors.initials: P
authors.lastname: Pachnis
authors.forename: Paul
authors.initials: P
authors.lastname: Andrews
authors.forename: Hideki
authors.initials: H
authors.lastname: Enomoto
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Milbrandt
authors.forename: Vassilis
authors.initials: V
authors.lastname: Pachnis
authors.forename: Mark C
authors.initials: MC
authors.lastname: Coles
authors.forename: Dimitris
authors.initials: D
authors.lastname: Kioussis
authors.forename: Henrique
authors.initials: H
authors.lastname: Veiga-Fernandes
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D017615:Enteric Nervous System / Q000196:embryology*; D041981:Gastrointestinal Tract / Q000196:embryology* / Q000294:innervation; D018507:Gene Expression Regulation, Developmental / Q000502:physiology; D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors / Q000378:metabolism*; D051379:Mice; D018613:Microscopy, Confocal; D009024:Morphogenesis / Q000502:physiology*; D010581:Peyer's Patches / Q000196:embryology*; D051096:Proto-Oncogene Proteins c-ret / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*
chemical_list: D051097:Glial Cell Line-Derived Neurotrophic Factor Receptors; D051096:Proto-Oncogene Proteins c-ret; C494999:Ret protein, mouse