G Protein-Coupled Receptor Signaling and Sphingosine-1-Phosphate Play a Phylogenetically Conserved Role in Endocrine Pancreas Morphogenesis

Ioannis Serafimidis; Scott Heximer; Dimitris Beis; Anthony Gavalas

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G Protein-Coupled Receptor Signaling and Sphingosine-1-Phosphate Play a Phylogenetically Conserved Role in Endocrine Pancreas Morphogenesis

机译：G蛋白偶联的受体信号和鞘氨醇-1-磷酸在内分泌胰腺形态发生中发挥系统发育上保守的作用。

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During development pancreatic endocrine cells migrate in a coordinated fashion. This migration is necessary to form fully functional islets, but the mechanisms involved remain unknown. Therapeutic strategies to restore β-cell mass and islet functionality by reprogramming endogenous exocrine cells would be strengthened from simultaneous treatments that enhance endocrine cell clustering. We found that endocrine progenitors respond to and regulate G protein-coupled receptor (GPCR) signaling in order to cluster in islets. Rgs4, a dedicated regulator of GPCR signaling, was specifically expressed in early epithelial endocrine progenitors of both zebrafish and mouse, and its expression in the mouse endocrine progenitors was strictly dependent upon Ngn3, the key specification gene of the endocrine lineage. Rgs4 loss of function resulted in defects in islet cell aggregation. By genetically inactivating Gα_i-mediated GPCR signaling in endocrine progenitors, we established its role in islet cell aggregation in both mouse and zebrafish. Finally, we identified sphingosine-1-phosphate (S1P) as a ligand mediating islet cell aggregation in both species acting through distinct but closely related receptors.

机译：在发育过程中，胰腺内分泌细胞以协调的方式迁移。这种迁移对于形成功能完整的胰岛是必需的，但是所涉及的机制仍然未知。通过增强内分泌细胞簇的同时治疗，可以加强通过重编程内源性外分泌细胞恢复β细胞质量和胰岛功能的治疗策略。我们发现内分泌祖细胞响应并调节G蛋白偶联受体（GPCR）信号传导以聚集在胰岛中。 Rgs4 是GPCR信号的专用调节剂，在斑马鱼和小鼠的早期上皮内分泌祖细胞中均特异性表达，其在小鼠内分泌祖细胞中的表达严格依赖于 Ngn3 ，是内分泌谱系的关键指标基因。 Rgs4 功能丧失导致胰岛细胞聚集缺陷。通过遗传失活内分泌祖细胞中的Gα_{i 介导的GPCR信号传导，我们确立了其在小鼠和斑马鱼胰岛细胞聚集中的作用。最后，我们确定了鞘氨醇-1-磷酸（S1P）作为介导胰岛细胞聚集的两种配体，它们通过不同但密切相关的受体起作用。} 展开▼

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《Molecular and Cellular Biology》 |2011年第22期|共12页

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Ioannis Serafimidis; Scott Heximer; Dimitris Beis; Anthony Gavalas;
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中图分类细胞生物学;

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1. Mutational analysis of the highly conserved ERY motif of the thromboxane A2 receptor: alternative role in G protein-coupled receptor signaling. [J] . Capra V, Veltri A, Foglia C, Molecular pharmacology. . 2004,第4期

机译：血栓烷A2受体的高度保守ERY基序的突变分析：在G蛋白偶联受体信号传导中的替代作用。

2. The N-terminus of the yeast G protein-coupled receptor Ste2p plays critical roles in surface expression, signaling, and negative regulation [J] . Uddin M. Seraj, Hauser Melinda, Naider Fred, Biochimica et biophysica acta. Biomembranes . 2016,第4期

机译：酵母G蛋白偶联受体Ste2p的N端在表面表达，信号传导和负调控中起关键作用

3. Signaling through fibroblast growth factor receptor 2b plays a key role in the development of the exocrine pancreas [J] . FRANCISCO MIRALLES, KEIICHI OZAKI Proceedings of the National Academy of Sciences of the United States of America . 1999,第11期

机译：通过成纤维细胞生长因子受体2b发出的信号在外分泌胰腺的发育中起关键作用

4. Mutations in G proteins and G protein-coupled receptors in human endocrine diseases [C] . Allen Spiege Colloque me?decine et recherche . 2006

机译：在人内分泌疾病中G蛋白和G蛋白偶联受体中的突变

5. G protein-coupled receptor signaling: Role of PAR2 in breast carcinoma metastasis and regulation of agonist-promoted internalization of P2Y1 receptors. [D] . Glast, Dionne Renee. 2009

机译：G蛋白偶联受体信号传导：PAR2在乳腺癌转移中的作用和激动剂促进的P2Y1受体内在化的调节。

6. G Protein-Coupled Receptor Signaling and Sphingosine-1-Phosphate Play a Phylogenetically Conserved Role in Endocrine Pancreas Morphogenesis [O] . Ioannis Serafimidis, Scott Heximer, Dimitris Beis, 2011

机译：G蛋白偶联的受体信号和鞘氨醇-1-磷酸在内分泌胰腺形态发生中发挥系统发育上保守的作用。

7. G Protein-Coupled Receptor Signaling and Sphingosine-1-Phosphate Play a Phylogenetically Conserved Role in Endocrine Pancreas Morphogenesis ▿ [O] . Serafimidis, Ioannis, Heximer, Scott, Beis, Dimitris, 2011

机译：G蛋白偶联的受体信号和鞘氨醇-1-磷酸在内分泌胰腺形态发生中发挥系统发育上保守的作用。 ▿

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5. Compound, methods for modulating g protein-coupled crf receptor function, for treating a snc disorder or disease, for locating crf receptors in tissue section samples, for inhibiting the binding of crf to a crf¹ receptor and for alter signal transduction activity of a crf¹ receptor and pharmaceutical composition [P] . 外国专利： BR0108363A . 2004-02-10

机译：化合物，调节g蛋白偶联的crf受体功能，治疗snc疾病或疾病，在组织切片样品中定位crf受体，抑制crf与crf¹受体结合以及改变crf¹受体的信号转导活性的方法和药物组合物

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G Protein-Coupled Receptor Signaling and Sphingosine-1-Phosphate Play a Phylogenetically Conserved Role in Endocrine Pancreas Morphogenesis

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