State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-Sen University, 54 Xianlie Road, Guangzhou, China.
Curr Mol Med. 2013 Jul;13(6):959-67. doi: 10.2174/1566524011313090067.
The extracellular signal-regulated kinase (ERK) is one of the three major types of mitogen-activated protein kinases. Previous studies showed that ERKs mediate various signaling pathways for cell proliferation, differentiation, survival and transformation in mammals. In the present study, we use goldfish as a model system and demonstrate that ERK kinases play important roles in promoting embryonic survival and regulate development of eye and trunk in vertebrates. ERKs are highly expressed in multiple tissues including lens epithelial cells, lens fiber cells, retina, brain, muscle and heart of adult goldfish. Injection of the dominant negative ERK mutant (DNM-ERK) into the fertilized eggs of goldfish significantly inhibited ERK activity at blastula stage, and completely blocked ERK activity at gastrula and later stages. As a result, the blastula cells were induced into apoptosis, and majority of the injected embryos were lethal at embryonic stages. At the molecular level, inhibition of ERK activity by DNM-ERKs suppressed phosphorylation of Bad at Ser-112 to promote apoptosis. Similar results were observed when MEK activity was inhibited by U0126 treatment. The survived embryos display significant abnormality in the phenotypes of both eye and trunk. Associated with the abnormality in the eye development, phosphorylation in Pax-6 and expression of HSF4 were significantly decreased and expression of the β-crystallin gene was also downregulated. These results provide novel information regarding the roles of ERKs in regulating vertebrate development.
细胞外信号调节激酶（ERK）是三种主要的丝裂原活化蛋白激酶之一。先前的研究表明，ERK 介导哺乳动物细胞增殖、分化、存活和转化的各种信号通路。在本研究中，我们以金鱼为模型系统，证明 ERK 激酶在促进胚胎存活和调节脊椎动物眼睛和躯干发育方面发挥重要作用。ERK 在包括晶状体上皮细胞、晶状体纤维细胞、视网膜、脑、肌肉和心脏在内的多种组织中高度表达。将显性负 ERK 突变体（DNM-ERK）注射到金鱼受精卵中，可显著抑制囊胚期 ERK 活性，并完全阻断原肠胚期及以后的 ERK 活性。结果，囊胚细胞被诱导凋亡，大多数注射胚胎在胚胎期死亡。在分子水平上，DNM-ERKs 抑制 ERK 活性，抑制 Bad 在 Ser-112 位点的磷酸化，从而促进凋亡。用 U0126 处理抑制 MEK 活性也观察到类似的结果。存活的胚胎在眼睛和躯干的表型上均显示出明显的异常。与眼睛发育异常相关，Pax-6 的磷酸化和 HSF4 的表达显著降低，β-晶体蛋白基因的表达也下调。这些结果为 ERK 在调节脊椎动物发育中的作用提供了新的信息。
