State Key Laboratory of Ophthalmology, Zhongshan Ophthalmic Center, Sun Yat-sen University, 54 Xianlie Road, Guangzhou, 510060, China.
Curr Mol Med. 2013 Jan;13(1):228-37.
The c-Jun N-terminal kinases (JNKs) constitute one of the three major types of mitogen-activated protein kinases. Previous studies showed that JNK mediates multiple signaling transduction pathways implicated in cell proliferation, differentiation, inflammation, stress response and apoptosis in mammals. In the present study, we use goldfish as a model system and demonstrate that JNK kinases are necessary to promote embryonic survival and regulate eye development in vertebrates. During goldfish development, JNK1 and JNK2 are expressed at every stage from cleavage to hatching larvae. JNK3 is turned on at the gastrulation stage and then expressed at similar level to that of JNK2. JNK1 activity remains slightly fluctuated during different developmental stages. Inhibition of JNK activity caused massive apoptosis of blastula cells and significant death of goldfish embryos, which are associated with altered expression of the anti-apoptotic regulator, Mcl-1 and the proapoptotic regulator, Bak. These results provide novel information regarding the mechanisms by which JNKs promote embryonic survival. In addition, the embryos that survived inhibition of JNK activity displayed severe phenotype in the eye with clear microphthalmia and lens coloboma. To confirm that the observed phenotype is derived from JNK activity deficiency, we expressed JNK dominant negative mutant (DNM-JNK) in goldfish. Expression of DNM-JNK also caused similar phenotypes with altered expression of pax-6, Sox-2 and β-crystallin. Together, our results demonstrate that JNKs play important roles in promoting survival of vertebrate embryos and regulating development of vertebrate eye.
c-Jun N-末端激酶（JNKs）是丝裂原活化蛋白激酶（MAPK）三大类型之一。先前的研究表明，JNK 介导了多种信号转导途径，这些途径与哺乳动物的细胞增殖、分化、炎症、应激反应和细胞凋亡有关。在本研究中，我们以金鱼为模型系统，证明 JNK 激酶在脊椎动物中促进胚胎存活和调节眼睛发育是必需的。在金鱼发育过程中，JNK1 和 JNK2 从卵裂到孵化幼虫的各个阶段都有表达。JNK3 在原肠胚形成阶段被激活，然后与 JNK2 表达水平相似。JNK1 的活性在不同发育阶段略有波动。JNK 活性的抑制导致囊胚细胞大量凋亡和金鱼胚胎的显著死亡，这与抗凋亡调节剂 Mcl-1 和促凋亡调节剂 Bak 的表达改变有关。这些结果为 JNK 促进胚胎存活的机制提供了新的信息。此外，抑制 JNK 活性后存活的胚胎在眼睛中表现出严重的表型，表现为小眼和晶状体裂。为了证实观察到的表型是源自 JNK 活性缺乏，我们在金鱼中表达了 JNK 显性负突变体（DNM-JNK）。DNM-JNK 的表达也导致了类似的表型，同时伴随着 pax-6、Sox-2 和β-晶状体蛋白表达的改变。总之，我们的结果表明 JNK 在促进脊椎动物胚胎存活和调节脊椎动物眼睛发育方面发挥着重要作用。
