Valapala Mallika, Edwards Malia, Hose Stacey, Hu Jianfei, Wawrousek Eric, Lutty Gerard A, Zigler J Samuel, Qian Jiang, Sinha Debasish
Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Maryland 21287, USA.
National Eye Institute, National Institutes of Health, Bethesda, Maryland 20892, USA.
Sci Rep. 2015 Mar 4;5:8755. doi: 10.1038/srep08755.
We have previously reported that in the Nuc1 rat, which has a spontaneous mutation in Cryba1 (the gene encoding βA3/A1-crystallin), astrocytes exhibit decreased Notch signaling, leading to reduced promoter activity for glial fibrillary acidic protein (GFAP). Interestingly, in both Nuc1 astrocytes and in wild type astrocytes following knockdown of Cryba1, vascular endothelial growth factor (VEGF) secretion is decreased. This has led us to explore signaling mediators that could be regulated by βA3/A1-crystallin to modulate both GFAP and VEGF. Several studies have shown that the signal transducer and activator of transcription 3 (STAT3) is involved in the co-regulation of GFAP and VEGF. We show that STAT3 and βA3/A1-crystallin may co-regulate each other in astrocytes. Such co-regulation would create a positive feedback circuit; i.e., in the cytosol of astrocytes, βA3/A1-crystallin is necessary for the phosphorylation of STAT3, which then dimerizes and translocates to the nucleus to form DNA-binding complexes, activating transcription of Cryba1. This stoichiometric co-regulation of STAT3 and Cryba1 could potentiate expression of GFAP and secretion of VEGF, both of which are essential for maintaining astrocyte and blood vessel homeostasis in the retina. Consistent with this idea, Cryba1 knockout mice exhibit an abnormal astrocyte pattern and defective remodeling of retinal vessels.
我们之前报道过，在Nuc1大鼠中，Cryba1（编码βA3/A1-晶体蛋白的基因）存在自发突变，星形胶质细胞的Notch信号传导减弱，导致胶质纤维酸性蛋白（GFAP）的启动子活性降低。有趣的是，在Nuc1星形胶质细胞以及Cryba1基因敲低后的野生型星形胶质细胞中，血管内皮生长因子（VEGF）的分泌均减少。这促使我们探索可能受βA3/A1-晶体蛋白调控的信号转导介质，以调节GFAP和VEGF。多项研究表明，信号转导和转录激活因子3（STAT3）参与了GFAP和VEGF的共同调节。我们发现，STAT3和βA3/A1-晶体蛋白可能在星形胶质细胞中相互共同调节。这种共同调节会形成一个正反馈回路；即，在星形胶质细胞的胞质溶胶中，βA3/A1-晶体蛋白是STAT3磷酸化所必需的，磷酸化后的STAT3会二聚化并转移至细胞核形成DNA结合复合物，从而激活Cryba1的转录。STAT3和Cryba1的这种化学计量共同调节可增强GFAP的表达和VEGF的分泌，这两者对于维持视网膜中星形胶质细胞和血管的稳态都至关重要。与此观点一致的是，Cryba1基因敲除小鼠表现出异常的星形胶质细胞模式和视网膜血管重塑缺陷。
