Differential RET Signaling Pathways Drive Development of the Enteric Lymphoid and Nervous Systems
Differential RET Signaling Pathways Drive Development of the Enteric Lymphoid and Nervous Systems
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DOI：
10.1126/scisignal.2002734
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发表时间：
2012-07-31
影响因子：
7.3
通讯作者：
Veiga-Fernandes, Henrique
中科院分区：
文献类型：
--
作者：
Patel, Amisha;Harker, Nicola;Veiga-Fernandes, Henrique
在胃肠道的早期发育过程中，通过受体酪氨酸激酶RET的信号传导是淋巴器官（Peyer’s patch）形成的起始和肠神经元的肠神经支配所必需的。RET信号通过胶质细胞系来源的神经营养因子（GDNF）家族受体发生，该受体是存在于同一细胞中的共受体（顺式信号传导）。目前尚不清楚反式中的RET信号是否具有生物学作用，该信号通过来自其他细胞的共受体在体外发生。我们发现造血细胞的初始聚集形成淋巴细胞簇是通过粘附介导的淋巴组织启动物（LTin）细胞的阻滞以ret依赖、趋化因子独立的方式发生的。这个起始阶段不需要淋巴组织诱导细胞。LTin细胞对反式中所有RET配体都有反应，需要其他细胞的因子，而肠神经元中的RET仅由顺式中GDNF激活。此外，遗传和分子方法表明，LTin细胞中的多种RET反应是由编码RET及其共受体的基因的不同表达模式决定的。我们的研究表明，LTin细胞的反式RET反应决定了肠淋巴器官形态发生的初始阶段，并提示RET和Gfra的差异共表达可以控制RET信号的特异性。
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 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.