Gene-environment interactions target MAP3K1 signaling in eyelid morphogenesis [Developmental Biology]

June 24th, 2015 by Mongan, M., Meng, Q., Wang, J., Kao, W. W.-Y., Puga, A., Xia, Y.

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 MAP3K1 signaling is a focal point of gene-environment crosstalk. Dioxin exposure, acting through the aryl hydrocarbon receptor (AHR), blocks eyelid closure in genetic mutants in which MAP3K1 signaling is attenuated, but does not disturb this developmental program in either wild type or mutant mice with attenuated EGFR or WNT signaling. Exposure also markedly inhibits 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 environmental pollutant exposure can increase the risk of developmental abnormalities driven by specific gene alterations.