Xia Ying, Kao Winston W-Y
Department of Environmental Health, Center for Environmental Genetics, University of Cincinnati Medical Center, OH 45267-0056, USA.
Biochem Pharmacol. 2004 Sep 15;68(6):997-1001. doi: 10.1016/j.bcp.2004.05.028.
Tissue morphogenesis during development is regulated by growth factors and cytokines, and is characterized by constant remodeling of extracellular matrix in response to signaling molecules. MEK kinase 1 (MEKK1) is a mitogen-activated protein kinase (MAPK) kinase kinase originally identified as an upstream activator for several MAPK pathways. During mouse embryogenesis, MEKK1 controls cell shape changes and formation of actin stress fibers that are required for sealing epidermis in the embryos in a process known as eyelid closure. MEKK1-null mice display eye-open at birth (EOB), a phenotype found also in mice impaired in activin, a subgroup of the transforming growth factor beta (TGFbeta) family, or in epidermal growth factor receptor (EGFR) or its ligand TGFalpha, or in transcription factor c-Jun. Molecular analyses have revealed at least two signaling mechanisms in the control of eyelid closure. One is originated from the activins and is transduced through MEKK1, leading to transcription-independent actin stress fiber formation and transcription-dependent keratinocyte migration. Another is the TGFalpha/EGFR signal that is transduced through a MEKK1-independent pathway to the activation of the ERK MAPK, which also leads to keratinocyte migration. c-Jun might serve as a connection between the two pathways. As embryonic eyelid closure is a specific morphogenetic process that is easily detectable, genetic mutant mice with EOB will be ideal models to understand the signaling mechanisms in the control of epithelial cell migration and the morphogenetic process of epithelial sheet movement.
发育过程中的组织形态发生受生长因子和细胞因子调控，其特征是细胞外基质响应信号分子而不断重塑。MEK激酶1（MEKK1）是一种丝裂原活化蛋白激酶（MAPK）激酶激酶，最初被鉴定为几种MAPK途径的上游激活剂。在小鼠胚胎发育过程中，MEKK1控制细胞形状变化和肌动蛋白应力纤维的形成，这些对于胚胎表皮在称为眼睑闭合的过程中密封是必需的。MEKK1基因敲除小鼠出生时眼睛睁开（EOB），这种表型也出现在转化生长因子β（TGFβ）家族的一个亚组激活素、表皮生长因子受体（EGFR）或其配体TGFα、或转录因子c-Jun受损的小鼠中。分子分析揭示了至少两种控制眼睑闭合的信号机制。一种源自激活素，并通过MEKK1转导，导致不依赖转录的肌动蛋白应力纤维形成和依赖转录的角质形成细胞迁移。另一种是TGFα/EGFR信号，它通过不依赖MEKK1的途径转导至ERK MAPK的激活，这也导致角质形成细胞迁移。c-Jun可能作为这两种途径之间的联系。由于胚胎眼睑闭合是一个易于检测的特定形态发生过程，具有EOB的基因敲除小鼠将是理解上皮细胞迁移控制中的信号机制和上皮片运动形态发生过程的理想模型。
