Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis
Mig-6 is required for appropriate lung development and to ensure normal adult lung homeostasis
复制标题
DOI：
10.1242/dev.032979
复制
发表时间：
2009-10-01
期刊：
影响因子：
4.6
通讯作者：
DeMayo, Francesco J.
中科院分区：
文献类型：
--
作者：
Jin, Nili;Cho, Sung-Nam;DeMayo, Francesco J.
有丝分裂原诱导基因 6 [Mig-6； Errfi1（ErbB 受体反馈抑制剂 1）； RALT（受体相关晚期转导器）；基因 33] 是一种普遍表达的衔接蛋白，含有 CRIB、SH3 和 14-3-3 相互作用结构域，并已被证明可以负调节 EGF 信号传导。 Mig-6 的消融会导致部分致死表型，其中幸存的小鼠患上退行性关节疾病和多个器官的肿瘤。我们已经确定，Mig-6(-/-) 小鼠的早期致死发生在围产期，小鼠的肺部发育异常。 Mig-6(-/-) 肺 (E15.5-P3) 的组织学检查显示间隔减少、气道过度分支、肺泡 II 型细胞增生和血管形成紊乱。在新生儿Mig-6(-/-)肺中，气道上皮细胞增殖增加，但血管细胞凋亡增加。成年 Mig-6(-/-) 小鼠出现慢性阻塞性肺疾病 (COPD) 的特征；然而，当成年小鼠中 Mig-6 被诱导消融 (Mig-6(d/d)) 时，肺部却恢复正常。在 H441 人细支气管上皮细胞中敲低 MIG-6 会增加磷酸 EGFR 和磷酸 AKT 水平以及细胞增殖，而在人肺微血管内皮 (HMVEC-L) 细胞中敲低 MIG-6 会促进其凋亡。这些结果表明，Mig-6 是产前和围产期肺部发育所必需的，部分是通过调节 EGF 信号传导以及维持适当的肺血管化来实现的。
Mitogen-inducible gene 6 [Mig-6; Errfi1 (ErbB receptor feedback inhibitor 1); RALT (receptor-associated late transducer); gene 33] is a ubiquitously expressed adaptor protein containing CRIB, SH3 and 14-3-3 interacting domains and has been shown to negatively regulate EGF signaling. Ablation of Mig-6 results in a partial lethal phenotype in which surviving mice acquire degenerative joint diseases and tumors in multiple organs. We have determined that the early lethality in Mig-6(-/-) mice occurs in the perinatal period, with mice displaying abnormal lung development. Histological examination of Mig-6(-/-) lungs (E15.5-P3) revealed reduced septation, airway over-branching, alveolar type II cell hyperplasia, and disturbed vascular formation. In neonatal Mig-6(-/-) lungs, cell proliferation increased in the airway epithelium but apoptosis increased in the blood vessels. Adult Mig-6(-/-) mice developed features of chronic obstructive pulmonary disease (COPD); however, when Mig-6 was inducibly ablated in adult mice (Mig-6(d/d)), the lungs were normal. Knockdown of MIG-6 in H441 human bronchiolar epithelial cells increased phospho-EGFR and phospho-AKT levels as well as cell proliferation, whereas knockdown of MIG-6 in human lung microvascular endothelial (HMVEC-L) cells promoted their apoptosis. These results demonstrate that Mig-6 is required for prenatal and perinatal lung development, in part through the regulation of EGF signaling, as well as for maintaining proper pulmonary vascularization.