Birth defects in human populations occur with an approximate frequency of 3 percent of all live births, often as a result of unknown or poorly understood causes. The long-term goal of our research is to understand the mechanisms of fetal development and the genesis of birth defects. Towards this goal, we have used genetically modified mice to study embryonic eyelid closure, an essential morphogenetic event of the mammalian eye. This event, involving epithelial cell migration that leads to fusion of the upper and lower eyelids, is a significant model for fundamental developmental processes, such as palate fusion and neural tube closure, whereby an opening in the epithelium is closed by morphogenetic forces. Our studies have shown that embryonic eyelid closure is a developmental threshold trait regulated by an exceptionally complex genetic network;diverse lesions that disrupt the network will result in failure to meet the threshold and consequently cause a defect in ontogenesis. We have identified MAP3 kinase 1 (MAP3K1) as an integral component of this network. Eyelid closure depends on Map3k1 as the major genetic locus and a series of """"""""weaker"""""""" alleles with graded strength. Although unveiling the genetic contribution to eyelid closure is the subject of extensive research, the environmental factors that may shift the threshold, and the genetic variations that may determine sensitivity to a particular environmental agent, are largely unknown. This R21 exploratory proposal will test the idea that eyelid closure is a multifactorial developmental threshold depending on complex interactions of genetic and environmental factors. We will use Map3k1 as a model gene and dioxin as a model compound to test the hypothesis supported by preliminary data that allelic Map3k1 deletion is a genetic risk factor that predisposes environmental insults for congenital eye disorders. In three Specific Aims, we will use genetic mutant mice to evaluate whether Map3k1 allelic deletion increases susceptibility to eyelid defects by in utero dioxin exposure;in the exposed fetuses, we will investigate the gene-environment interaction mechanisms that lead to eyelid developmental defects;we will use compound genetic mutant mice to assess whether dioxin acts through the Ah receptor-MAP3K1 axis to affect eyelid morphogenesis. If successful, we will establish an experimental paradigm to study gene-environment interaction mechanisms underlying multifactorial birth defects and chart a path to test for these connections of many other genetic and environmental risk factors. Furthermore, we will expand our understanding on the mechanisms of genetic susceptibility to dioxin induced birth defects. This information will help to direct epidemiology and risk assessment efforts towards a subgroup of susceptible individuals with pre-existing genetic conditions. In addition, unraveling the mechanisms of gene- environment interaction will have significant public health benefits, because it provides an avenue for using genetic information to stratify the allocation of environmental intervention for disease prevention.
This project will investigate the gene-environment interaction mechanisms that control embryonic eyelid development and test the novel idea that genetic risk factor predisposes environmental insults for congenital eye disorders. Since embryonic eyelid closure responds to a developmental program conserved in mammals, we will use mouse models to explore the genetic and environmental basis that confer birth defects due to failure of embryonic eyelid closure. Results will help us to better understand the basic roots of congenital diseases related to failed closure a hole in the epithelium by morphogenetic force, such as cleft palate and spina bifida;they may also facilitate the identification of high-risk populations for targeted interventions.
|Mongan, Maureen; Meng, Qinghang; Wang, Jingjing et al. (2015) Gene-Environment Interactions Target Mitogen-activated Protein 3 Kinase 1 (MAP3K1) Signaling in Eyelid Morphogenesis. J Biol Chem 290:19770-9|
|Yousaf, Rizwan; Meng, Qinghang; Hufnagel, Robert B et al. (2015) MAP3K1 function is essential for cytoarchitecture of the mouse organ of Corti and survival of auditory hair cells. Dis Model Mech 8:1543-53|