Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis.
Gene-environment interactions determine the biological outcomes through mechanisms that are poorly understood. Mouse embryonic eyelid closure is a well defined model to study the genetic control of developmental programs. Using this model, we investigated how exposure to dioxin-like environmental pollutants modifies the genetic risk of developmental abnormalities. Our studies reveal that mitogen-activated protein 3 kinase 1 (MAP3K1) signaling is a focal point of gene-environment cross-talk. Dioxin exposure, acting through the aryl hydrocarbon receptor (AHR), blocked eyelid closure in genetic mutants in which MAP3K1 signaling was attenuated but did not disturb this developmental program in either wild type or mutant mice with attenuated epidermal growth factor receptor or WNT signaling. Exposure also markedly inhibited c-Jun phosphorylation in Map3k1(+/-) embryonic eyelid epithelium, suggesting that dioxin-induced AHR pathways can synergize with gene mutations to inhibit MAP3K1 signaling. Our studies uncover a novel mechanism through which the dioxin-AHR axis interacts with the MAP3K1 signaling pathways during fetal development and provide strong empirical evidence that specific gene alterations can increase the risk of developmental abnormalities driven by environmental pollutant exposure.
['Mongan|Maureen|M|', 'Meng|Qinghang|Q|', 'Wang|Jingjing|J|', 'Kao|Winston W-Y|WW|', 'Puga|Alvaro|A|', 'Xia|Ying|Y|']
D000818:Animals D004147:Dioxins D004622:Embryo, Mammalian D004785:Environmental Pollutants D004848:Epithelium D005143:Eyelids D018507:Gene Expression Regulation, Developmental D059647:Gene-Environment Interaction D048031:JNK Mitogen-Activated Protein Kinases D048728:MAP Kinase Kinase Kinase 1 D051379:Mice D009024:Morphogenesis D010766:Phosphorylation D018336:Receptors, Aryl Hydrocarbon D015398:Signal Transduction
gene-environment interaction mitogen-activated protein 3 kinase 1 (MAP3K1) signaling morphogenesis embryonic eyelid closure dioxin aryl hydrocarbon receptor (AhR) (AHR) c-Jun N-terminal kinase (JNK)