Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling
Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling
复制标题
1-磷酸鞘氨醇通过刺激 EGFR 信号传导刺激发育中的大鼠眼睑闭合
DOI：
10.1126/scisignal.aat1470
复制
发表时间：
2018-10-23
影响因子：
7.3
通讯作者：
Wang, Jian
中科院分区：
文献类型：
--
作者：
Bian, Ganlan;Yu, Caiyong;Wang, Jian
1-磷酸鞘氨醇刺激EGFR配体的动员，以驱动大鼠胚胎的眼睑闭合。为了防止眼睛在出生和出生后早期发育过程中受到损伤，许多哺乳动物的眼睑在胚胎发育过程中迁移到角膜上并融合。这一过程的失败会导致出生时睁眼（EOB）表型，从而导致永久性角膜损伤。Bian等人在一株表现出EOB表型的转基因大鼠中发现了Spns2的插入突变，该突变编码鞘氨醇1-磷酸（S1P）转运蛋白。体内和体外眼睑组织外植体实验表明，S1P通过促进参与细胞迁移的蛋白的激活和刺激表皮生长因子受体（EGFR）信号传导来促进眼睑闭合。这些结果确定了一个复杂的信号和反馈事件网络，通过该网络，S1P刺激金属蛋白酶依赖的EGFR配体的动员，以协调胚胎发生期间眼睑的迁移和融合。在许多哺乳动物中，眼睑在胚胎发生时在眼睛上移动并融合，以保护角膜在出生和早期生命中免受损伤。影响表皮生长因子受体（EGFR）信号通路的功能丧失突变导致啮齿动物出生时睁眼（EOB）表型。我们在一株表现出EOB表型的转基因大鼠中发现了Spinster同源物2 （Spns2）的插入突变。Spns2是一种从细胞中释放S1P的Spns2转运蛋白，在野生型大鼠胚胎发育中的眼睑尖端富集。Spns2的表达或用S1P或几种EGFR配体中的任何一种处理，在体内和体外组织外植体中恢复了EOB Spns2突变体的表型，并在原代角化细胞中恢复了突变体的应激纤维的形成。S1P通过受体S1PR1、S1PR2和S1PR3发出信号，激活细胞外信号调节激酶（ERK）和egfr依赖性丝裂原激活蛋白激酶激酶1 (MEKK1) -c-Jun信号。S1P还以依赖于EGFR信号传导的方式诱导转录因子MAL的核易位。MAL和c-Jun刺激miR-21和miR-222的表达，这两个microrna都靶向金属蛋白酶抑制剂TIMP3，从而促进金属蛋白酶的活性。金属蛋白酶ADAM10和ADAM17通过切割膜锚定形式的EGF以释放配体来刺激EGFR信号传导。我们的研究结果勾勒出一个网络，通过一个复杂的机制，S1P通过几个细胞内和细胞外分子之间的反馈来激活EGFR信号，从而促进发育中的大鼠眼睑融合。
Sphingosine 1-phosphate stimulates the mobilization of EGFR ligands to drive eyelid closure in rat embryos. A signaling lipid directs eyelid morphogenesis To prevent the eye from being damaged during birth and early postnatal development, the eyelids of many mammals migrate over the cornea and fuse during embryonic development. Failure of this process causes an eyes-open-at-birth (EOB) phenotype, which leads to permanent corneal damage. Bian et al. identified an insertional mutation in Spns2, which encodes a sphingosine 1-phosphate (S1P) transporter, in a strain of transgenic rats exhibiting the EOB phenotype. Experiments in vivo and with eyelid tissue explants in vitro showed that S1P stimulated eyelid closure by promoting the activation of proteins involved in cell migration and by stimulating epidermal growth factor receptor (EGFR) signaling. These results identify a complex network of signaling and feedback events through which S1P stimulates the metalloprotease-dependent mobilization of EGFR ligands to coordinate the migration and fusion of the eyelids during embryogenesis. In many mammals, the eyelids migrate over the eye and fuse during embryogenesis to protect the cornea from damage during birth and early life. Loss-of-function mutations affecting the epidermal growth factor receptor (EGFR) signaling pathway cause an eyes-open-at-birth (EOB) phenotype in rodents. We identified an insertional mutation in Spinster homolog 2 (Spns2) in a strain of transgenic rats exhibiting the EOB phenotype. Spns2, a sphingosine 1-phosphate (S1P) transporter that releases S1P from cells, was enriched at the tip of developing eyelids in wild-type rat embryos. Spns2 expression or treatment with S1P or any one of several EGFR ligands rescued the EOB Spns2 mutant phenotype in vivo and in tissue explants in vitro and rescued the formation of stress fibers in primary keratinocytes from mutants. S1P signaled through the receptors S1PR1, S1PR2, and S1PR3 to activate extracellular signal–regulated kinase (ERK) and EGFR-dependent mitogen-activated protein kinase kinase kinase 1 (MEKK1)–c-Jun signaling. S1P also induced the nuclear translocation of the transcription factor MAL in a manner dependent on EGFR signaling. MAL and c-Jun stimulated the expression of the microRNAs miR-21 and miR-222, both of which target the metalloprotease inhibitor TIMP3, thus promoting metalloprotease activity. The metalloproteases ADAM10 and ADAM17 stimulated EGFR signaling by cleaving a membrane-anchored form of EGF to release the ligand. Our results outline a network by which S1P transactivates EGFR signaling through a complex mechanism involving feedback between several intra- and extracellular molecules to promote eyelid fusion in the developing rat.