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

作者：Patel Amisha; Harker Nicola; Moreira Santos Lara; Ferreira Manuela; Alden Kieran; Timmis Jon; Foster Katie; Garefalaki Anna; Pachnis Panayotis; Andrews Paul; Enomoto Hideki; Milbrandt Jeffrey; Pachnis Vassilis; Coles Mark C; Kioussis Dimitris; Veiga Fernandes Henrique^*

来源：Science Signaling, 2012, 5(235): ra55.

DOI：10.1126/scisignal.2002734

During the early development of the gastrointestinal tract, signaling through the receptor tyrosine kinase RET is required for initiation of lymphoid organ (Peyer%26apos;s patch) formation and for intestinal innervation by enteric neurons. RET signaling occurs through glial cell line-derived neurotrophic factor (GDNF) family receptor a 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.

• 出版日期2012-7-31
• 单位河北医科大学