华南理工王键教授团队:首次发现胚胎发育中眼睑闭合调控机制
作者:Ganlan Bian, Caiyong Yu, Ling Liu, Chao Fang, Kun Chen, Pan Ren, Qian Zhang, Fangfang Liu, Kun Zhang, Qian Xue, Jie Xiang, Hongmin Guo, Jun Song, Yu Zhao, Wutian Wu, Sookja K. Chung, Ruixia Sun, Gong Ju, Jian Wang
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2018-11-07 23:40:09
近日,华南理工大学医学院王键教授带领的神经生物学团队在世界上首次发现胚胎发育中眼睑闭合的调控机制。在胚胎发育的过程中,眼睑需要闭合以保护眼球和视力的正常发育,直到胎儿出生后才会睁开眼睛。神经生物学团队发现,眼睑闭合是由S1P-EGFR信号转导通路调控的。S1P作为第二信使,在细胞内合成后,通过与其特异性结合的转运体运输到细胞外,以自分泌或旁分泌的形式激活EGF受体,最终使眼睑闭合。当Spns2基因(编码S1P转运体)发生突变时,就会导致胎儿的眼睑不能闭合,引起视觉受损。
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Sphingosine 1-phosphate stimulates eyelid closure in the developing rat by stimulating EGFR signaling
作者:Ganlan Bian, Caiyong Yu, Ling Liu, Chao Fang, Kun Chen, Pan Ren, Qian Zhang, Fangfang Liu, Kun Zhang, Qian Xue, Jie Xiang, Hongmin Guo, Jun Song, Yu Zhao, Wutian Wu, Sookja K. Chung, Ruixia Sun, Gong Ju, Jian Wang
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2018-11-07 23:40:09
导语
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.
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