Department of Environmental and Public Health Sciences, College of Medicine, University of Cincinnati, Cincinnati, OH 45267-0056, USA.
Cells. 2021 Dec 23;11(1):34. doi: 10.3390/cells11010034.
The MAP3K1 is responsible for transmitting signals to activate specific MAP2K-MAPK cascades. Following the initial biochemical characterization, genetic mouse models have taken center stage to elucidate how MAP3K1 regulates biological functions. To that end, mice were generated with the ablation of the entire gene, the kinase domain coding sequences, or ubiquitin ligase domain mutations. Analyses of the mutants identify diverse roles that MAP3K1 plays in embryonic survival, maturation of T/B cells, and development of sensory organs, including eye and ear. Specifically in eye development, loss-of-function was found to be autosomal recessive for congenital eye abnormalities, but became autosomal dominant in combination with and mutations. Additionally, mutation increased eye defects with an exposure to environmental agents such as dioxin. Data from eye developmental models reveal the nexus role of MAP3K1 in integrating genetic and environmental signals to control developmental activities. Here, we focus the discussions on recent advances in understanding the signaling mechanisms of MAP3K1 in eye development in mice and in sex differentiation from human genomics findings. The research works featured here lead to a deeper understanding of the in vivo signaling network, the mechanisms of gene-environment interactions, and the relevance of this multifaceted protein kinase in disease etiology and pathogenesis.
MAP3K1 负责传递信号以激活特定的 MAP2K-MAPK 级联。在最初的生化特征描述之后，遗传小鼠模型成为阐明 MAP3K1 如何调节生物学功能的中心。为此，生成了整个基因、激酶结构域编码序列或泛素连接酶结构域突变的缺失的小鼠。对突变体的分析确定了 MAP3K1 在胚胎存活、T/B 细胞成熟和感官器官（包括眼睛和耳朵）发育中的多种作用。特别是在眼睛发育中，发现失功能是常染色体隐性遗传的先天性眼睛异常，但与和突变结合时变为常染色体显性遗传。此外，突变增加了与环境剂（如二恶英）暴露相关的眼睛缺陷。来自眼睛发育模型的数据揭示了 MAP3K1 在整合遗传和环境信号以控制发育活动中的核心作用。在这里，我们重点讨论了最近在理解 MAP3K1 在小鼠眼睛发育和人类基因组学发现中的性别分化中的信号转导机制方面的进展。这里介绍的研究工作加深了对体内信号网络、基因-环境相互作用机制以及这种多功能蛋白激酶在疾病病因和发病机制中的相关性的理解。
